HIGH-QUALITY clinical data is essential to maintaining trust in influenza vaccination programs, especially as the global death toll from seasonal flu approaches 700,000 annually, disproportionately affecting older adults. A new editorial argues that without rigorous standards in trial design and regulatory benchmarks, flu vaccine efficacy may gradually erode, a phenomenon known as “biological creep.”
Vaccines approved through randomized controlled trials (RCTs) are considered the gold standard. These large-scale studies demonstrate superiority or noninferiority to an existing vaccine in preventing influenza. However, many new flu vaccines follow an alternative route: smaller Phase III immunogenicity trials that measure immune response via hemagglutinin inhibition (HAI) titers. While an HAI titer of 40 is historically considered protective in 50% of individuals, mounting evidence suggests this surrogate marker is inadequate on its own. The HAI assay shows high interlaboratory variability, does not fully reflect performance across all age groups or vaccine platforms such as mRNA, and may not correlate with meaningful clinical protection in real-world settings.
Regulators now require that efficacy trials begin at the time of vaccine licensure, even for immunogenicity-based approvals, reinforcing the need for data that goes beyond immune markers. Still, within efficacy trials, concerns remain. Noninferiority studies, though ethically and financially practical, pose risks when manufacturers use suboptimal comparators or generous margins. These choices may enable vaccine licensure without demonstrating true equivalence to the most effective standard-of-care vaccines.
The article underscores the need for regulatory vigilance. All stakeholders, regulators, clinicians, patients, and industry, share a common goal: that flu vaccines, especially those recommended preferentially for vulnerable populations, deliver substantial clinical benefit. Ensuring robust, transparent, and scientifically valid trial designs is crucial to safeguarding public health and preventing the slow erosion of vaccine effectiveness.
Reference:
Manning JE et al. First Among Equals: The Case for High-quality Clinical Data in Influenza Vaccines. Clin Infect Dis. 2025. doi:10.1093/cid/ciaf290.
