Advancing Toward More Effective Influenza Vaccines

Seasonal influenza (flu) remains a significant public health issue, and researchers are placing renewed emphasis on understanding how immune history, vaccine composition, and antigen design influence protection. New results from the National Institutes of Health (NIH) uncover the physiological processes that cause differences in vaccine responsiveness and highlight opportunities for the creation of the next-generation flu vaccines.¹

How Immune Imprinting Shapes Flu Vaccine Responses

A pivotal NIH study evaluated immune responses to seasonal flu vaccination in 39 pairs of identical twins, aiming to figure out the relative influence of genetics and individual exposure history on vaccine-induced immunity. The researchers observed that most twin pairs exhibited highly similar "subtype biases"; in other words, their immune systems preferentially reactivated responses to previously encountered flu strains, even though their infection histories differed.¹

The findings imply that immune imprinting, sometimes termed "original antigenic sin," significantly shapes how people respond to flu vaccines over their lifetimes. If an individual’s immune system is programmed to focus on certain flu subtypes at an early age, then later vaccinations may continue to support those patterns instead of changing them.

The concept aligns with the findings of a 2025 review, which examined the achievements and challenges in developing improved flu vaccines.² The review focuses on the necessity of understanding how sequential exposures—by infection or vaccination—affect the combination of humoral and cellular immunity over a long period of time. Cohort studies have shown that antibody quality, memory B-cell formation, and an individual's cross-reactive immunity are influenced by the flu situations they have encountered before.

These findings add to the demand for flu vaccines that can overcome immune bias and thus provide broader, longer-lasting protection. According to the review, future-generation concepts could also involve targeting the virus with conserved viral epitopes, engineering improved antigen designs, and enhancing T-cell responses to achieve cross-strain coverage.²

Improving Vaccine Platforms Beyond Egg-Based Production

Beyond immune imprinting, manufacturing methods remain a major driver of vaccine effectiveness challenges. For instance, the production of flu vaccine in eggs, which has been the method of choice for the last several years, may introduce 'egg-adaptive' mutations that alter viral antigens so they become less well matched to circulating strains. According to CDC data, non-egg-based platforms, such as cell-based and recombinant vaccines, have demonstrated greater antigenic fidelity to circulating flu viruses.³

These platforms do not have the problem of egg-induced mutations and can be more effective, particularly, in seasons when the circulating strain changes quickly. For older adults and other populations with weaker immune system responses, these improved technologies may offer clinically meaningful benefits.

Exploring Novel Mucosal Vaccination Strategies

New studies are also revealing different ways to improve mucosal vaccines and adjuvants. One such study on animals showed that researchers have tested the enhancement of intranasal vaccines with dendritic-cell-derived extracellular vesicles that dramatically escalate both mucosal and systemic immune responses in the treated animals, which makes them resistant to the same as well as different viral challenges.⁴ Because flu infection begins in the respiratory mucosa, intranasal vaccination may provide broader frontline protection by inducing secretory IgA and localized memory immune responses.

Implications for Pharmacists and Public Health

For pharmacists, these scientific advancements have practical implications. As frontline vaccinators and patient educators, pharmacists will play a critical role in communicating the differences between available flu vaccine technologies, especially as more non–egg-based or next-generation options enter the market. Pharmacists may be key to identifying patient populations who could benefit most from enhanced vaccine platforms, such as older adults, immunocompromised individuals, and those with a history of repeated vaccinations who may experience immune imprinting. Pharmacists also continue to be trusted sources for counseling on vaccine expectations, including the importance of annual vaccination even as improved formulations are in development.

Continued articulation of the field will see the combination of immune-related knowledge, up-to-date production techniques, and cutting-edge vaccine technologies providing a revitalized potential for the development of flu vaccines that are more potent, long-lasting, and broadly protective. The studies now underway underscore a future where flu vaccines will be able to take into consideration each person's immune history, be free of antigenic mismatch, and provide more consistent population-wide protection. Until then, annual flu vaccination remains one of the best ways to lower the risk of serious disease and prevent hospitalizations.

REFERENCES

1. Building a better flu vaccine. National Institutes of Health (NIH). Published January 13, 2025. Accessed December 4, 2025. https://www.nih.gov/news-events/nih-research-matters/building-better-flu-vaccine

2. Ostrowsky JT, Vestin NC, Mehr AJ, et al. Accomplishments and challenges in developing improved influenza vaccines: an evaluation of three years of progress toward the milestones of the influenza vaccines research and development roadmap. Vaccine. 2025;61:127431-127431. doi:10.1016/j.vaccine.2025.127431

3. CDC. CDC study points to potential benefits of newer flu vaccines. Influenza (Flu). Published February 22, 2024. Accessed December 4, 2025. https://www.cdc.gov/flu/whats-new/2023-2024-flu-vaccine-benefits.html

4. Novel Flu Vaccine Adjuvant Improves Protection Against Influenza Viruses. Office of the Provost. Published July 8, 2025. Accessed December 4, 2025. https://provost.gsu.edu/2025/07/08/novel-flu-vaccine-adjuvant/