Lyme disease infects about 476,000 people in the United States each year and can lead to severe complications such as ongoing fatigue and joint issues. However, no human vaccine is yet commercially available. Vaccination needs to be safe, and the number of immunizations should be limited, while still providing protection. Surface antigens from infectious agents, even in their recombinant forms, often lack the immunogenicity needed for effective vaccines.
In a new study published in Nature Communications entitled, “Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine,” researchers from Tufts University have engineered Lyme bacterial protein, CspZ, to produce a robust immune response in preclinical studies in mice for vaccine development. The work was led by an international team, which included researchers from Tufts University, Baylor College of Medicine, University of Texas at Austin, and Riga Stradins University in Latvia.
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. Using structure-based design, the authors solved the crystal structure of a mutated CspZ (CspZ-YA), which lacks the ability to bind to host complement factor H, a regulator of immune response.
The study generated CspZ-YA point mutations that train 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. Compared to CspZ-YA, CspZ-YA mutants required a lower immunization frequency to protect mice from Lyme disease-associated inflammation and bacterial colonization.
Current Lyme disease vaccines in clinical trials target the Lyme protein, OspA, that is produced abundantly when bacteria are in ticks. However, OspA production is reduced after bacteria enter mammalian hosts, thereby requiring repeated boosters to maintain protective levels of antibodies. The authors emphasize that exploring alternative vaccine candidates, such as CspZ, addresses this gap.
“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,” said Lin.
The researchers plan to explore several applications for their patented vaccine strategy against Lyme disease, including working with commercial partners to develop platforms for the safe testing and delivery of engineered CspZ protein-based vaccines in 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.”