Lyme disease continues to pose a growing public health concern, infecting an estimated 476,000 people each year in the United States alone, according to the Centers for Disease Control and Prevention (CDC). The tick-borne illness, caused by Borrelia burgdorferi bacteria, can lead to severe long-term complications, including debilitating fatigue, joint pain, and neurological issues, if left untreated. Despite decades of research and near breakthroughs, no human vaccine has yet proven commercially viable.
A team of international researchers led by Tufts University may be turning the tide with the development of a promising new vaccine target, a bacterial protein known as CspZ, which plays a critical role in helping the Lyme bacteria evade the immune system.
Targeting Lyme Bacteria’s Stealth Mechanism
The study, published April 7 in Nature Communications, highlights a novel engineered version of the CspZ protein that can effectively stimulate a strong and targeted immune response in pre-clinical models.
“We’ve known for years that CspZ would be an ideal vaccine target because it’s produced in abundance during infection,” said Yi-Pin Lin, associate professor of infectious disease and global health at the Cummings School of Veterinary Medicine at Tufts University. “But in its natural form, it doesn’t trigger a strong immune response. The immune system simply doesn’t ‘see’ it.”
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The key challenge, according to Lin, was to redesign the protein structure so that the immune system could recognize and respond to it effectively. Through precise alterations to CspZ’s genetic code, Lin’s team exposed previously hidden regions of the protein—regions the immune system can now detect and attack.
Breakthrough in Protein Engineering
After multiple design iterations, the research team successfully engineered a form of CspZ that produces a robust immune response in mice. Encouragingly, the modified protein also showed similar activation patterns in human immune cells, suggesting the potential for cross-species efficacy.
To further understand how the redesigned protein works, researchers employed three-dimensional structural imaging. The analysis revealed that the immune response zeroes in on CspZ’s “Achilles heel”—a vulnerable, exposed portion of the protein that remains hidden in its native form.
“This exposed region becomes a clear target for antibodies,” explained Lin. “When vaccinated, the host’s immune system is primed to recognize and neutralize the Lyme bacteria by focusing on this vulnerable spot.”
Extended Protection With Fewer Boosters
In addition to enhancing immune visibility, the researchers also improved the thermal stability of the modified CspZ protein, which is essential for its performance as a vaccine in real-world conditions.
“What we also found through structure-based vaccine design is that we could further modify CspZ to make the molecule more stable at body temperature,” said Lin. “This allows the engineered protein to persist longer in the body and sustain continuous antibody production, which could reduce the need for frequent booster shots.”
This advancement could make a future Lyme vaccine not only effective but also more practical and convenient for public use.
An International Collaborative Effort
The research was carried out by a multidisciplinary and international team, including:
- Yi-Pin Lin, Tufts University
- Maria Elena Bottazzi and Wen-Hsiang Chen, Texas Children’s Hospital Center for Vaccine Development, Baylor College of Medicine
- Ching-Lin Hsieh, formerly at the University of Texas
- Kalvis Brangulis, Latvian Biomedical Research and Study Centre and Riga Stradins University
Their collaboration was essential to overcoming the complex biochemical and immunological challenges that have long stalled Lyme vaccine development.
“Vaccine development is a very long process, and when we’re doing experiments, 90% of the time they don’t work,” said Lin. “But having a vaccine is better than having no vaccine, so having collaborators who see problems differently helped us overcome challenges at each step.”
Next Steps: Clinical Trials and Ecological Applications
With a promising vaccine target in hand, the team now plans to explore a range of applications for the engineered CspZ protein, including:
- Human clinical trials in partnership with commercial vaccine developers
- Potential wildlife-based immunization programs, particularly targeting white-footed mice, which are primary reservoirs for the Borrelia bacteria
- Investigations into delivery platforms that could make the vaccine safe and scalable for broader public health deployment
The approach also supports One Health principles, recognizing the interconnectedness of human, animal, and environmental health in controlling vector-borne diseases.
A Potential Turning Point in Lyme Disease Research
The development of a safe, effective Lyme disease vaccine would represent a critical milestone in public health, especially as climate change and ecological disruption expand the habitats of disease-carrying ticks. With CspZ emerging as a viable vaccine target, the work by Lin and colleagues brings new momentum to the field.
Research for this project was supported by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, and the U.S. Department of Defense Congressionally Directed Medical Research Programs.
If proven safe and effective in humans, a CspZ-based vaccine could be the long-awaited breakthrough needed to curb Lyme disease and protect hundreds of thousands each year from a debilitating and growing health threat.
