The End of Immunobridging: How the FDA's Shift to Correlate of Protection Will Transform Vaccine Approval Strategies

For decades, vaccine developers have relied on immunobridging to speed up approval of updated vaccines. This approach allowed regulators to approve new or modified vaccines by comparing immune responses to those of already-approved vaccines, avoiding lengthy and costly efficacy trials. Now, the U.S. Food and Drug Administration (FDA) is moving away from this shortcut. Instead, it proposes a more rigorous system based on establishing a Correlate of Protection (CoP). This change will reshape how vaccine trials are designed and how regulatory strategies are developed.

If you work in vaccine development, clinical research, or regulatory affairs, understanding this shift is essential. It will affect timelines, costs, and the scientific evidence needed to bring vaccines to market.

What Is Immunobridging and Why Has It Been Used?

Immunobridging, sometimes called bio-bridging, is a method that infers vaccine effectiveness by comparing immune responses rather than directly measuring disease prevention. Instead of conducting large-scale trials to see if a vaccine prevents illness, sponsors show that their vaccine produces antibody levels similar to a reference vaccine already proven effective.

This approach relies on the assumption that a certain immune response level, such as a geometric mean titer (GMT) of antibodies, predicts real-world protection. Regulators accept data showing the new vaccine’s immune response is "non-inferior" to the reference, allowing faster approval.

Why Immunobridging Worked Until Now

• Speed: It avoids repeating large, expensive efficacy trials.

• Flexibility: It supports rapid updates for seasonal vaccines like flu shots.

• Practicality: It was especially useful during emergencies, such as COVID-19 booster approvals.

  
  

However, immunobridging depends heavily on the assumption that antibody levels directly correlate with protection. This assumption is not always clear or consistent across different vaccines or populations.

The FDA’s Move Toward Correlate of Protection

The FDA now wants to replace immunobridging with a system based on formally established Correlates of Protection. A CoP is a specific immune marker or threshold scientifically proven to predict vaccine effectiveness against disease.

This approach requires:

• Clear identification of immune markers that reliably indicate protection.

• Standardized assays to measure these markers consistently.

• Robust data linking immune response to clinical outcomes across diverse populations.

  
  

By focusing on CoPs, the FDA aims to improve the scientific rigor of vaccine approvals and reduce uncertainty about how immune responses translate to real-world protection.

What This Means for Vaccine Development and Regulatory Strategy

More Rigorous Clinical Programs

Developers will need to design trials that not only measure immune responses but also establish or confirm CoPs. This may involve:

• Larger or more complex studies to link immune markers with actual disease prevention.

• Use of standardized laboratory methods to ensure data comparability.

• Inclusion of diverse populations to validate CoPs across age groups, ethnicities, and risk factors.

  
  

Potential Impact on Timelines and Costs

Moving from immunobridging to CoP-based approval could increase the time and expense of clinical development. Sponsors may need to:

• Conduct additional studies to identify or validate CoPs.

• Invest in assay development and validation.

• Engage earlier and more frequently with regulators to align on CoP criteria.

  
  

Opportunities for Innovation

While more demanding, this shift encourages innovation in vaccine science. Developers can:

• Explore new immune markers beyond antibodies, such as T-cell responses.

• Develop vaccines targeting broader or more durable protection.

• Use CoPs to support approvals in populations where direct efficacy trials are challenging.

  
  

Examples Illustrating the Shift

COVID-19 Vaccines

During the pandemic, immunobridging allowed rapid approval of boosters by comparing antibody responses to original vaccines. Now, as the FDA seeks CoPs, vaccine makers must provide stronger evidence linking immune markers to protection against variants and severe disease.

Influenza Vaccines

Seasonal flu vaccines have long used immunobridging. Establishing CoPs could improve how updates are evaluated, potentially leading to vaccines that better match circulating strains and provide longer-lasting immunity.

Preparing for the Future

Vaccine developers and regulatory teams should:

• Start incorporating CoP research into early clinical development.

• Collaborate with academic and regulatory partners to identify reliable immune markers.

• Plan for more comprehensive data packages that go beyond antibody titers.

• Stay informed about evolving FDA guidance and expectations.

  
  

Summary

The FDA’s move away from immunobridging toward Correlate of Protection-based approval marks a significant change in vaccine regulation. This new approach demands stronger scientific evidence linking immune responses to actual protection, which will affect how vaccines are developed, tested, and approved. While this may increase development complexity and costs, it promises more reliable and effective vaccines in the long run.