Meeting the unmet need for a vaccine is the top priority for researchers studying Lyme disease, which infects about 476,000 people in the U.S. each year and can come with severe complications such as ongoing fatigue and joint issues. Vaccine developers have come close to success, but no human vaccine has yet been commercially viable.   

After decades of trial and error, a promising new target is emerging—the Lyme bacterial protein CspZ, which the bacteria use to evade detection from the body’s immune system. CspZ first emerged as a candidate while scientists were looking for proteins that might be evolutionarily conserved across different Lyme bacteria strains and so generate a broad protective response. 

“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.  

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. 

"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. 

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.”