Study Supports Safety of Trivalent Influenza Vaccines in Older Adults


The randomized, blinded trial evaluated the safety and reactogenicity of aIIV3 and HD-IIV3 in adults 65 and older.

Kenneth Schmader, MD,

Kenneth Schmader, MD,

A new study evaluating the safety and reactogenicity of trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) in older adults reported that both are acceptable to use in the prevention of influenza (flu).

Currently licensed in the US for adults aged 65 years and older, both vaccines have shown to be more effective than trivalent standard-dose, unadjuvanted inactivated influenza vaccines (SD-IIV3).

However, no previous research has directly compared the safety between aIIV3 and HD-IIV3 in the same trial.

To do just that, a team led by Kenneth Schmader, MD, Department of Medicine, Duke University School of Medicine, conducted a randomized, blinded, multicenter trial during the 2017-2018 and 2018-2019 flu seasons.

“The primary objective (statistical end point) was to compare proportions of participants with moderate-to-severe injection-site pain following aIIV3 vs HD-IIV3,” the investigators wrote. 

“A coprimary objective was to compare serious adverse events (SAEs) and adverse events of clinical interest (AECI) after each vaccine,” they continued.

The Study

The team evaluated a total of 757 patients ≥65 years old (mean age, 72). A majority were woman (55%) and White individuals (78%).

The population was then randomized 1:1 to receive either aIIV3 or HD-IIV3.

Participants who received a vaccine during the 2017-2018 flu season and were subsequently evaluated were ineligible to be evaluated during the 2018-2019 season. Therefore, all participants represented unique individuals.

The primary outcome of moderate-to-severe injection-site pain and 14 other solicited reactions were measured within 8 days of vaccination and using a noninferiority test.

Serious adverse events and adverse events of clinical interest were measured between days 1-43.

The investigators also measured health-related quality of life (HRQOL) scores before and after vaccination (days 1 and 3). These scores were then compared between study groups.

The Results

Final data indicated that the proportion of patients who reported moderate-to-severe injection-site pain following reception of aIIV3 (n = 12; 3.2%) was noninferior compared with HD-IIV3 (n = 22; 5.8% [difference −2.7%; 95% CI, −5.8 to 0.4]).

Furthermore, 10 solicited reactions (fever, chills, vomiting, diarrhea, nausea, headache, myalgia, redness, swelling, shoulder pain on side of vaccination) met noninferiority criteria for aIIV3, while 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not.

“It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3,” the investigators wrote.

Further, no participant sought medical care of a vaccine reaction. No adverse events of clinical interest were observed in this population.

The team reported that 9 participants had at least 1 serious adverse event following aIIV3 injection (2.4%; 95% CI, 1.1-4.5) and 3 participants had at least 1 severe adverse event after HD-IIV3 (0.8%; 95% CI, 0.2-2.2). And yet, the investigators determined that no severe adverse event was associated with vaccination.

Additionally, HRQOL scores were considered not clinical meaningful pre- and post-vaccination and between groups.

Conclusion and Perspective

Schmader and his team concluded that both vaccines are acceptable to use in adults of older age.

However, they acknowledged that their study was powered for a single-outcome of injection-site pain, a limitation in their analysis. Furthermore, they did not address the safety of administering allV3 or HD-IIV3 with additional vaccines in the same visit.

“The safety of adjuvanted influenza vaccines has been a topic of public interest,” they wrote. “Similar clinical safety profiles support the conclusion that concerns about differences in safety between aIIV3 and HD-IIV3 need not be a factor when choosing between them.”

The study, “Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults,” was published online in JAMA Network Open.

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