Outer surface protein A (OspA) is a molecule found on the surface of Borrelia burgdorferi, the bacterium responsible for causing Lyme disease. This protein plays a specialized role in the life cycle of the spirochete, primarily within its tick vector. OspA’s function made it a highly effective target for the first generation of licensed human vaccines aimed at preventing Lyme infection. Understanding this protein is necessary to grasp the biology of the disease and the specific mechanism used by the early vaccine to block transmission.
The Structure and Function of OspA
OspA is classified as an abundant lipoprotein, meaning it has an attached lipid anchor that embeds it into the outer membrane of the Borrelia burgdorferi bacterium. Its physical structure is complex, forming an unusual dumbbell shape composed primarily of 21 consecutive anti-parallel \(\beta\)-strands and a single \(\alpha\)-helix. This folding pattern allows the protein to be highly exposed on the bacterial surface, making it accessible to the immune system.
The protein is expressed at its highest levels when the Borrelia spirochete is residing in the midgut of the unfed Ixodes tick. Here, OspA’s function is to help the bacterium survive and persist during the tick’s dormant phases. It accomplishes this by mediating the spirochete’s attachment to the tick’s gut lining, specifically by binding to the TROSPA receptor (Tick Receptor for OspA). This adhesion is necessary for the long-term colonization of the tick vector.
OspA’s Critical Role in the Tick-to-Host Transmission Cycle
The life cycle of Borrelia burgdorferi depends on a carefully timed genetic switch that allows the bacterium to move from the tick to the mammalian host. When an infected tick begins to take a blood meal, environmental cues like rising temperature and altered nutrients trigger the spirochete to alter its protein expression profile. This change is necessary for successful transmission.
During this process, the expression of OspA is rapidly and profoundly downregulated. This downregulation is a prerequisite for the bacterium to detach from the tick gut wall and migrate to the salivary glands. Simultaneously, the bacterium begins to upregulate the expression of other outer surface proteins, most notably Outer surface protein C (OspC).
The reciprocal expression of OspA and OspC serves as a biological signal: high OspA indicates colonization in the unfed tick, while high OspC indicates infective readiness in the feeding tick. Because OspA expression is shut down during transmission, the protein is largely absent once the bacteria enter the human body. This biological timing makes OspA an excellent target for transmission prevention, but a poor diagnostic marker for established infection.
Natural Host Immune Response to OspA
During a natural infection transmitted by an infected tick, the human immune system recognizes the OspA protein and produces antibodies against it. However, the level and timing of this antibody response are typically insufficient to clear the initial infection or prevent its spread. This inefficiency is a direct consequence of the spirochete’s regulatory switch upon entering the host.
Since OspA is rapidly downregulated and replaced by OspC, the few OspA molecules present are quickly shed or masked. By the time the host’s adaptive immune system generates a substantial OspA-specific antibody response, the bacteria have already disseminated throughout the body, expressing the OspC protein instead.
The History and Mechanism of the OspA Vaccine
The unique life cycle of OspA was exploited in the development of the first licensed human Lyme disease vaccine, LYMErix, which received approval in the United States in 1998. This recombinant vaccine introduced the OspA protein into the human body. The immunization regimen involved three doses and demonstrated high efficacy, with clinical trials showing a 76% reduction in Lyme disease incidence after the full series.
The protection utilized a mechanism known as transmission-blocking immunity, which is distinct from how most vaccines function. The vaccine did not prevent the tick from biting or clear an established infection in the human body. Instead, it trained the immune system to generate high concentrations of OspA-specific antibodies circulating in the bloodstream.
When an infected tick fed on a vaccinated person, it ingested the blood meal containing these anti-OspA antibodies. These antibodies bound to the OspA protein on the spirochetes while they were still in the tick’s midgut. This binding neutralized the OspA protein and was bactericidal, effectively killing the Borrelia before they could migrate to the salivary glands and be transmitted to the host. LYMErix was voluntarily withdrawn from the market in 2002, but its mechanism remains foundational to current vaccine research.