For decades, scientists have searched for a way to outsmart Lyme disease, a stealthy infection that affects nearly half a million people each year in the U.S. Now, a breakthrough may be within reach.
Researchers have zeroed in on a bacterial protein called CspZ that helps the Lyme bacteria hide from the immune system. By cleverly reengineering this protein to expose its most vulnerable part, they’ve created a version that can trigger a powerful immune response in lab models. This discovery could pave the way for a long-awaited human vaccine—and potentially even curb the disease at its wildlife source.
Urgent Need for a Human Lyme Vaccine
Developing an effective vaccine remains a top priority for researchers tackling Lyme disease, which affects an estimated 476,000 people in the United States each year. The illness can lead to serious long-term symptoms, including chronic fatigue and joint pain. Although several vaccine candidates have come close to success, none have yet reached commercial use for humans.
Now, after decades of research and setbacks, scientists are focusing on a promising new target: a bacterial protein called CspZ. This protein helps the Lyme bacteria hide from the immune system, making it harder for the body to detect and fight the infection. CspZ first caught scientists’ attention because it appears to be conserved across many strains of Lyme bacteria, suggesting it could help create a broadly protective vaccine.
Engineering a Hidden Immune Trigger
“We’ve known for years that CspZ would be an ideal vaccine target because it’s produced in abundance during infection, but the challenge was that in its natural form, the protein doesn’t trigger a strong immune response,” said Yi-Pin Lin, an associate professor of infectious disease and global health at Cummings School of Veterinary Medicine at Tufts University. “To get around this, we needed to engineer the protein’s structure to reveal hidden regions that the immune system could recognize and respond to effectively.”
It took several attempts, but Lin and his collaborators identified the specific tweaks to CspZ’s genetic code to create an engineered protein that produced a robust immune response in pre-clinical studies in mice. With this success and seeing that mice and human immune cells react similarly to the modified CspZ protein—giving hope that this could carry over to patients—the researchers now wanted to use three-dimensional imaging to better understand how their new vaccine target works.
Targeting Lyme’s Achilles Heel
Their latest study, appearing April 7 in the journal Nature Communications, shows that the modified CspZ triggers an immune response targeting the CspZ protein’s exposed “Achilles heel.” Normally, the native CspZ remains hidden from the immune system by binding to molecules responsible for detecting dangerous bacteria or parasites, making it inaccessible to immune defenses. However, the modified CspZ trains the immune system to produce antibodies that recognize CspZ’s exposed region in its altered form, making it much easier for the host’s white blood cells to find and eliminate Lyme disease-causing bacteria.
Making the Vaccine More Durable
“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, who is a co-corresponding author on the study. “This allows the engineered CspZ protein to persist longer in the body to promote continuous production of protective antibodies, which significantly reduces how many vaccine booster shots are needed.”
The work was led by an international team of experts, including Lin at Tufts University; Maria Elena Bottazzi and Wen-Hsiang Chen at the Texas Children’s Hospital Center for Vaccine Development, Baylor College of Medicine; Ching-Lin Hsieh, formerly at the University of Texas; and Kalvis Brangulis at the Latvian Biomedical Research and Study Centre and Riga Stradins University.
Next Steps: Trials and Wild Reservoirs
The researchers plan to explore several applications for their patented vaccine strategy against Lyme disease. This may include working with commercial partners to develop platforms for the safe testing and delivery of engineered CspZ protein-based vaccines by conducting human clinical trials or immunizing natural populations of the wild, white-footed mice that carry the bacteria that ticks transfer to infect humans.
“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.”
Reference: “Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine” by Kalvis Brangulis, Jill Malfetano, Ashley L. Marcinkiewicz, Alan Wang, Yi-Lin Chen, Jungsoon Lee, Zhuyun Liu, Xiuli Yang, Ulrich Strych, Dagnija Tupina, Inara Akopjana, Maria-Elena Bottazzi, Utpal Pal, Ching-Lin Hsieh, Wen-Hsiang Chen and Yi-Pin Lin, 7 April 2025, Nature Communications.
DOI: 10.1038/s41467-025-58182-x
Research reported in this article was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases and the U.S. Department of Defense Congressionally Directed Medical Research Programs. Complete information on authors, funders, methodology, limitations and conflicts of interest is available in the published paper.
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