Lyme disease is the most common vector-borne illness in the Northern Hemisphere, caused by the bacterium Borrelia burgdorferi. It is primarily transmitted to humans through the bite of an infected black-legged tick, specifically the Ixodes species. The increasing geographic spread and prevalence of these ticks highlights the need for effective preventative measures. The history of efforts to create a human vaccine against this infection is complex, marked by a brief success followed by a decades-long absence from the market.
The First Human Vaccine and Its Withdrawal
The first and only human Lyme disease vaccine approved in the United States was licensed in 1998. This product, an Outer Surface Protein A (OspA)-based vaccine, had shown approximately 76% to 78% efficacy against infection after the required three-dose primary series. Despite its effectiveness and safety profile in clinical trials, the manufacturer voluntarily withdrew the product from the market in 2002.
This withdrawal was not prompted by a mandatory regulatory recall based on confirmed safety issues. The U.S. Food and Drug Administration (FDA) investigated claims that the vaccine caused chronic arthritis but found insufficient evidence to establish a causal link. Instead, the decision was primarily driven by low consumer demand and poor sales performance. Public controversy, negative media coverage, and class-action lawsuits regarding perceived side effects created an environment of public skepticism. Ultimately, the combination of required short-term boosters and public resistance led to the end of the first human Lyme vaccine.
Mechanism of Lyme Disease Prevention via Vaccination
The approach used by the original vaccine and current candidates is distinct from many other vaccines, as it aims to stop the infection inside the tick. The vaccine works by introducing the human body to the Outer Surface Protein A (OspA), which is a protein found on the surface of the Borrelia burgdorferi bacteria. This immunization prompts the person’s immune system to produce high levels of anti-OspA antibodies.
When an infected tick bites a vaccinated person, it ingests the human blood containing these protective antibodies. OspA is preferentially expressed by the bacteria while they are residing in the tick’s midgut, where they prepare to migrate into the human host. Once the blood meal enters the tick, the ingested antibodies bind to the OspA on the surface of the bacteria.
This binding effectively neutralizes or eliminates the Borrelia before they can exit the tick’s gut and travel into the human bloodstream. This unique transmission-blocking mechanism is a form of “reservoir-targeted” vaccination. Current animal vaccines for dogs utilize a similar mechanism, often targeting OspA and OspC proteins.
Emerging Human Vaccine Candidates
There is now a highly advanced vaccine candidate in the final stage of clinical development. The investigational vaccine, known as VLA15, is a collaboration between Valneva and Pfizer. Like its predecessor, VLA15 is a multivalent protein subunit vaccine that targets the Borrelia OspA protein.
A major advancement of VLA15 is its broader coverage, as it targets six different serotypes of OspA. This is intended to offer protection against the most common pathogenic Borrelia species found across both North America and Europe. The candidate is currently being evaluated in a large-scale Phase 3 clinical trial, which enrolled over 9,400 participants aged five years and older.
This Phase 3 trial, known as VALOR (Vaccine Against Lyme for Outdoor Recreationists), is testing a dosing schedule that includes a primary series, typically administered over several months, followed by booster doses. The primary vaccination series has been completed for participants, who will continue to be monitored through the end of the 2025 Lyme disease season. Pending positive efficacy and safety data from this final trial phase, the manufacturers aim to submit regulatory applications to the FDA and European agencies in 2026.
The target population for VLA15 is expected to include individuals five years of age and older who live in or frequently visit high-risk areas where Lyme disease is endemic. The development of this new candidate marks a significant step toward providing a tool to prevent the most common vector-borne disease in the Northern Hemisphere. The expectation is that if approved, this vaccine will reintroduce a preventative option that has been absent for over two decades.