Correlates of Protection

BARDA, NIAID, Fred Hutch scientists lead broad collaboration to identify “correlates of protection” that could aid COVID-19 vaccine development

August 10, 2021

Correlates of Protection Photograph

A vaccine recipient’s antibody response in the first weeks after vaccination directly correlates with their reduced risk of symptomatic COVID-19 infection over the following three to four months, according to a new analysis from the Phase 3 trial of Moderna’s mRNA COVID-19 vaccine.

Because a “correlate of protection,” or CoP, is a statistically valid biomarker generated from very large clinical trials already done, it could potentially allow for development of additional vaccines or expand indications of current vaccines with fewer individuals needed in subsequent clinical trials.

The finding could speed additional indications of vaccines, which could be particularly beneficial for special populations – such as children, pregnant women, immunocompromised people or people with underlying medical conditions – as well as accelerate assessment of vaccine efficacy against new variants of SARS-CoV-2. It also could potentially have broader applications in developing vaccines against other viral diseases. Additionally, it enables evaluation of new COVID-19 vaccines without enrolling as many participants in a traditional large study, which would be difficult when other vaccines are already in use.

The analysis of blood (serum) samples from 30,415 study volunteers who received either a Moderna mRNA COVID-19 vaccine or a placebo found that the level of neutralizing antibodies in serum four weeks after the first dose was an accurate marker for the individual’s protection against symptomatic COVID-19 infection over three to four months. Those who had antibody levels in the top 10 percent at day 29 after the first vaccine dose had 10 times lower risk for symptomatic COVID-19 over three to four months, according to the paper published online at medRxiv as a pre-print and not yet peer reviewed.

The study also looked at those same antibodies taken 57 days after the first dose and found that the measurements at day 29 were just as accurate and indicative of protection. This could potentially reduce the time required to evaluate either new vaccines or existing ones in new populations or after manufacturing requirements change or other modifications are made. These antibodies were found to be compelling biomarkers that may help inform future clinical study design.

Biomarkers are any characteristic about the human body that can be objectively measured and evaluated – such as height or weight or certain molecules in the bloodstream or organs - that capture what is happening in a cell or an organism at a given moment. A CoP is a type of biomarker that can be measured in blood or other human bodily fluid samples and accurately predicts how well a vaccine will protect against infection or illness.

Studies of clinical samples from the other primarily U.S. government-supported Phase 3 clinical trials of COVID-19 vaccines developed by Johnson & Johnson, AstraZeneca, Sanofi, and Novavax to identify correlates of protection are also underway. Each of these trials enrolled approximately 30,000 to 60,000 people. Moving forward, rather than conducting similarly large trials that can take months or years to complete, CoP could shorten the development timeline needed to show efficacy of new COVID-19 vaccines or to expand their use.

The Correlates of Protection project is a collaboration led by scientists at BARDA along with colleagues from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the Fred Hutchinson Cancer Research Center. The collaboration builds on research done around the world by government, academic and private-sector groups. Their work includes:

  • Convening a group of virologists, immunologists, molecular biologists, statisticians and clinical trial experts to establish the project goals and the standards for evaluating potential CoP.
  • Developing and validating specific tests that can be used for consistent measurement of immune responses to the SARS-CoV-2 virus. The U.S. government helped obtain raw materials and facilitated technology transfer from academic labs to commercial entities with higher capacity. The process used multiple technologies both for redundancy and to ensure comparable measurements from lab to lab.
  • Establishing a blinded sampling plan with vaccine manufacturers that uses serum samples taken during their clinical trials.
  • Processing the serum samples and collecting data that could be shared with and analyzed by statisticians and vaccine manufacturers, with results published in peer-reviewed scientific journals.

ABOUT THE TEAM:

The Correlates of Protection project is a collaboration led by scientists at BARDA; the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH); and Fred Hutch. This paper was co-authored by BARDA’s Ruben Donis and Richard Koup of NIAID, and Peter Gilbert of the Fred Hutchinson Cancer Research Center. BARDA scientists Christopher Houchens, Karen Martins, Lakshmi Jayashankar, Flora Castellino, and Chuong Huynh are among the co-authors, along with Weiping Deng, Jacqueline Miller, Rolando Pajon, and Honghong Zhou, from Moderna, Inc., and biostatisticians from six other academic centers.

Last Updated: August 10, 2021

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