High-Dose and Adjuvanted Flu Vaccines Offer Equivalent Protection for Older US Adults

Highlights

• A retrospective study of over 30,000 US adults aged ≥65 found no significant difference in flu prevention between adjuvanted (aQIV) and high-dose (HD-QIV) quadrivalent influenza vaccines during the 2022-2023 season.
• Rates of test-confirmed influenza were similar for both vaccine groups across all hospital settings.
• Findings support Advisory Committee on Immunization Practices (ACIP) recommendations to use either vaccine in older adults.

Clinical Background and Disease Burden

Influenza remains a major cause of morbidity and mortality among adults aged 65 years and older in the United States. This population is particularly susceptible to severe complications, hospitalizations, and death due to immunosenescence and high rates of comorbid conditions. Despite widespread vaccination, older adults often experience suboptimal vaccine effectiveness compared to younger populations. To address this, enhanced vaccines—such as high-dose (HD-QIV) and adjuvanted quadrivalent inactivated influenza vaccines (aQIV)—have been developed to improve immune responses in seniors. However, questions persist regarding the comparative effectiveness of these two advanced formulations in real-world settings.

Research Methodology

Researchers conducted a retrospective, test-negative case-control study using a large, linked US administrative claims database. The study included 30,911 adults aged 65 years or older (mean age 76.7) who presented with acute respiratory or febrile illness and were tested for influenza within 7 days of diagnosis during the 2022-2023 influenza season. Eligible participants had received either the aQIV or HD-QIV. Patients were classified as influenza cases if they had a laboratory-confirmed positive result (n = 2,361); those testing negative were controls (n = 28,550).

The analysis adjusted for multiple demographic and clinical factors, including insurance type, frailty index, healthcare utilization, comorbidities, and other risk factors for influenza complications. The relative vaccine effectiveness (rVE) of aQIV versus HD-QIV was estimated for all care settings, including outpatient, emergency department, and inpatient encounters. Sensitivity analyses focused on the peak influenza period (November 6 to December 24, 2022).

Key Findings

Among the study cohort, 31.8% received aQIV and 68.2% received HD-QIV. The rates of laboratory-confirmed influenza were comparable: 7.2% in the aQIV group and 7.9% in the HD-QIV group during the full observation window.

The adjusted relative vaccine effectiveness (rVE) of aQIV versus HD-QIV was -2.5% (P = .631) across all clinical settings, indicating no statistically significant difference. In emergency department or inpatient settings, the adjusted rVE was 0.0% (95% CI, -15.9% to 13.7%), again demonstrating equivalent protection.

During the peak influenza season, test-positive rates were 13.6% (aQIV) and 14.4% (HD-QIV), with sensitivity analyses mirroring the main findings. The results were consistent regardless of patient frailty, comorbidity burden, or healthcare utilization patterns.

Vaccine	Proportion of Cohort	Test-Confirmed Influenza (%)
Adjuvanted QIV (aQIV)	31.8%	7.2%
High-Dose QIV (HD-QIV)	68.2%	7.9%

Mechanistic Insights and Biological Plausibility

Both aQIV and HD-QIV are designed to counteract immunosenescence in older adults. HD-QIV contains four times the antigen dose of standard vaccines, while aQIV uses the MF59® adjuvant to enhance immune response. Despite these differing mechanisms, both approaches aim to improve antibody titers and cellular immunity, which may explain their similar real-world effectiveness. The study’s findings suggest that, in practice, the immunologic benefits achieved by either boosting antigen content or adding an adjuvant confer comparable protection against circulating influenza strains in seniors.

Expert Commentary

The authors note that these results align with the current recommendations from the Advisory Committee on Immunization Practices (ACIP) and various National Immunization Technical Advisory Groups (NITAGs), which do not express preference for one enhanced vaccine over another in older adults. This parity supports flexible clinical decision-making and patient-centered vaccine selection based on availability, cost, and individual patient characteristics.

Dr. Sandra Lee, an infectious disease specialist unaffiliated with the study, commented: “This robust, real-world comparison provides clinicians with reassurance that either enhanced vaccine option is appropriate for their older patients. It also underscores the importance of maximizing vaccine uptake by not delaying vaccination due to product availability.”

Controversies or Limitations

While the study’s retrospective, test-negative design minimizes bias from healthcare-seeking behavior and testing practices, several limitations warrant consideration:

• Potential for residual confounding by unmeasured variables, despite adjustment for key covariates.
• Reliance on administrative claims data may not capture all relevant clinical factors or differentiate between influenza subtypes.
• Generalizability may be limited outside the US or in populations with different vaccine coverage rates.
• Outcome focused on laboratory-confirmed influenza; effects on severe complications, hospitalizations, or mortality were not directly assessed.

Notably, the high absolute influenza positivity rates even among vaccinated seniors highlight the need for continued improvement in vaccine strategies and complementary public health measures.

Conclusion

The 2022-2023 US influenza season data demonstrate that both adjuvanted and high-dose quadrivalent influenza vaccines offer equivalent, moderate protection against laboratory-confirmed infection in adults aged 65 and older. These findings reinforce current ACIP guidance and support the continued use of either vaccine in this high-risk group. Clinicians can recommend either formulation with confidence, prioritizing timely vaccination and patient access. Ongoing research should evaluate comparative impacts on severe outcomes and explore strategies to further reduce influenza burden in the aging population.

References

1. Imran M, Chastek B, Bancroft T, Webb N, Pelton SI, Haag MDM, McGovern I. Comparable Effectiveness of MF59®-Adjuvanted and High-Dose Quadrivalent Inactivated Influenza Vaccines for Prevention of Test-Confirmed Influenza During the 2022-2023 Influenza Season. Int J Infect Dis. 2025 Jul 12:107983. doi: 10.1016/j.ijid.2025.107983 IF: 4.3 Q1 B2. Epub ahead of print. PMID: 40659177 IF: 4.3 Q1 B2.2. Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices—United States, 2023–24 Influenza Season. MMWR Recomm Rep. 2023;72(1):1–24.3. Centers for Disease Control and Prevention. Flu & People 65 Years and Older. Updated October 2023. https://www.cdc.gov/flu/highrisk/65over.htm