Every year, influenza causes millions of infections worldwide and places a significant burden on healthcare systems. For vaccine developers, scientific innovation remains essential, but demonstrating value increasingly extends beyond generating positive clinical trial results.
Today’s regulators, public health authorities, national immunization technical advisory groups (NITAGs), payers, and healthcare decision-makers are increasingly focused on real-world performance. Efficacy trials are generally not required after each seasonal strain update, relying instead on immunogenicity and continuous monitoring of vaccine effectiveness in routine clinical practice. Yet generating real-world evidence is often far more complex than many stakeholders realize.
The challenge with influenza
Unlike many vaccine-preventable diseases, influenza is constantly changing.
Circulating strains vary from season to season, vaccine compositions are updated annually, and effectiveness can differ substantially depending on age groups, healthcare settings, and epidemiological conditions. A vaccine shown to be effective in a clinical trial may perform differently once introduced into routine clinical practice, and effectiveness may also vary from one season to the next.
This dynamic environment has driven increasing demand for robust real-world evidence that complements clinical development programs and supports decision-making after authorization.
For manufacturers, real-world effectiveness evidence is no longer a “nice to have”. It has become an important component of demonstrating vaccine value throughout the product lifecycle.
Why efficacy is only part of the story
Randomized clinical trials remain the foundation of vaccine development, providing critical evidence of safety and efficacy under controlled conditions. However, demonstrating efficacy in a clinical trial is only part of the story. Real-world effectiveness studies help determine how a vaccine performs in routine clinical practice across diverse populations, healthcare settings, and epidemiological conditions, and, specifically for influenza, across seasons.
This distinction matters because influenza vaccine performance can be influenced by multiple factors, including circulating strains, timing of vaccination, population characteristics, previous vaccination history, and healthcare-seeking behavior.
As a result, real-world evidence is increasingly used to support regulatory evaluation, public health recommendations, vaccination policies, and market access decisions.
The growing demand for brand-specific evidence
The evidence landscape has evolved considerably over the past decade.
Historically, influenza vaccine effectiveness studies often evaluated vaccination per vaccine type or platform, without distinguishing between products. Today, spurred by the advent of multiple vaccine technologies to choose from (e.g. adjuvanted, high-dose, recombinant, cell-based, live-attenuated), healthcare decision-makers are increasingly interested in understanding how specific vaccine brands and technologies perform in real-world settings. In addition, regulators are interested in vaccine effectiveness to inform the evolution of the benefit-risk balance. This shift has increased demand for brand-specific effectiveness evidence that can support regulatory, policy, clinical, and reimbursement decisions.
Large multinational studies across Europe have demonstrated the feasibility of generating brand-specific effectiveness estimates while also highlighting the operational and methodological complexity required to produce robust and credible results.
For vaccine developers, generating this level of evidence often requires access to extensive surveillance networks, multi-country study infrastructure, advanced epidemiological methodologies, and specialized analytical expertise.
Real-world evidence is only as strong as the study behind it
One of the biggest misconceptions about vaccine effectiveness research is that large datasets automatically produce reliable answers.
In practice, study design matters just as much as study size.
Observational effectiveness studies face numerous challenges, including differences in patient populations, healthcare access, vaccination behavior, and disease surveillance systems. Another layer of complexity to consider in influenza vaccine effectiveness studies is the fragmentation of influenza vaccine distribution. Across countries/regions, we find different brands of influenza vaccines, as there are different vaccine procurement pathways, which makes the accrual of the right sample size more challenging. Even well-designed studies require careful consideration of potential confounding factors and sources of bias. Research from the DRIVE consortium highlighted the importance of understanding and addressing confounding in multi-country influenza vaccine effectiveness studies to ensure estimates are suitable for regulatory and public health decision-making.
Experience from large influenza vaccine effectiveness networks has shown that generating decision-ready evidence requires far more than data collection. It requires careful study design, standardized methods, strong quality controls, and analytical approaches tailored to real-world data.
Without these elements, effectiveness estimates can be difficult to interpret and even harder to use for regulatory or policy decision-making.
Building evidence across the vaccine lifecycle
The most successful evidence-generation strategies begin long before a vaccine reaches the market.
Sponsors are increasingly thinking about real-world evidence as a continuum that supports development, authorization, post-authorization monitoring, and ongoing value demonstration.
This approach allows manufacturers to answer a range of critical questions:
- How does the vaccine perform in populations underrepresented in clinical trials?
- Does effectiveness vary by age group or risk profile?
- How does effectiveness change across different influenza seasons?
- Can effectiveness be demonstrated against severe outcomes such as hospitalization?
Answering these questions often requires combining multiple evidence-generation approaches, including post-authorization effectiveness studies in multiple populations, healthcare settings and seasons, systematic literature reviews and (network) meta-analyses. No single study can answer every effectiveness question, particularly in a disease area where vaccine performance can vary by age group, influenza season, circulating strain, and vaccine technology.
From DRIVE to COVIDRIVE to id.DRIVE: demonstrating the value of adaptable evidence-generation platforms
To address such real-world evidence needs, P95 Julius Clinical has coordinated a global study network since 2021, conducting brand-specific vaccine effectiveness studies through a public-private partnership called id.DRIVE. id.DRIVE stems from DRIVE, a European Commission IHI project that focused on brand-specific influenza vaccine effectiveness assessment in Europe (2017-2022), where P95 Julius Clinical also contributed as a key partner providing epidemiology support.
More than a decade of influenza and other viral pathogen vaccine effectiveness research at P95 Julius Clinical have highlighted a consistent theme: generating meaningful evidence requires flexibility, scientific rigor, and long-term commitment.
The COVID-19 pandemic further demonstrated the importance of adaptable surveillance and evidence-generation platforms. The evolution from DRIVE to COVIDRIVE and subsequently id.DRIVE highlights the value of adaptable surveillance and evidence-generation platforms. Originally established to monitor influenza vaccine effectiveness in Europe, DRIVE rapidly adapted during the COVID-19 pandemic by incorporating COVID-19-related data collection and analyses. Building on this foundation, COVIDRIVE was launched in 2020 to generate post-authorization COVID-19 vaccine effectiveness evidence. As new preventive products emerged, including RSV vaccines and monoclonal antibodies, and additional vaccines for respiratory and other infectious diseases progressed through development pipelines, the need arose for a broader, pathogen-agnostic platform. This led to the creation of id.DRIVE in 2024, expanding the COVIDRIVE scope beyond vaccine effectiveness studies and beyond COVID-19. The platform demonstrates how flexible, sustainable infrastructures can continuously evolve to address changing public health priorities and emerging evidence needs.
Running these large European effectiveness platforms requires deep understanding of vaccine epidemiology, infectious disease surveillance, study operations, data management, regulatory expectations, and stakeholder engagement. The platforms have shown how collaborative, multinational networks can generate actionable insights that support both public health and regulatory needs.
An increasingly important capability for vaccine developers
As expectations for real-world evidence continue to grow, vaccine manufacturers face increasing pressure to generate evidence that is scientifically robust, operationally feasible, and relevant to decision-makers.
The questions are becoming more complex, and the stakes are becoming higher.
Sponsors need partners who understand not only study execution, but also the broader evidence-generation strategy needed to support a vaccine throughout its lifecycle.
At P95 Julius Clinical, our teams have supported multinational influenza vaccine effectiveness studies, systematic reviews and (network) meta-analyses, and methodological research designed to generate robust real-world evidence. This experience provides a unique perspective on the scientific, operational, and regulatory challenges associated with measuring vaccine effectiveness at scale.
As influenza vaccine innovation continues to evolve, robust real-world evidence will play an increasingly important role in demonstrating value, informing policy, and ultimately improving public health outcomes.
