FOCUS Infectious Disease THE TO FIGHT TICKS TICKING CLOCK THE LYME DISEASE VACCINE'S COMEBACK STORY BY CINDY MEI ART BY DIYA NAIK 16 Yale Scientific Magazine December 2023 www.yalescientific.org
Infectious Disease FOCUS Tick spray might not be the first thing you think of when preparing to go backpacking. However, if gone undetected, these small arachnids can feed and feed, increasing the likelihood of transmission of dangerous bacteria. Named for the city of Lyme, Connecticut, where it was first detected, Lyme disease is most commonly spread by Ixodes ticks and is the most common tick-borne illness in the Northeast region of the United States. If left untreated, the disease can cause debilitating effects on the heart, joints, muscles, and nervous system. According to the CDC, reports of Lyme disease have doubled in the United States since 2000, reflecting a growing need for prevention. In 1993, the Yale Scientific Magazine reported on a novel vaccine being tested against Lyme disease (Vol. 67 No. 2). The writer, Emily Ho, estimated that the vaccine would be “available for the public sometime in 1995.” However, as of today, there are no Lyme disease vaccines available for humans. What went wrong? Revisiting the Past The story began in 1988, when Erol Fikrig—then a postdoctoral researcher— met with Richard Flavell, who was the newly appointed chair of immunobiology at the Yale School of Medicine. “We decided, why don’t we make a vaccine against Lyme disease?” said Fikrig, now the Waldemar von Zedtwitz Professor of Medicine at Yale. So, they started looking for a target. Lyme disease is caused by Borrelia burgdorferi, which is a pathogenic spirochete (a type of slender, spiral-shaped bacteria). It was known that a key part of protection against Lyme disease in animals is mediated by humoral immunity, a type of immune response that can be passive or active. In active immunity, B cells (a type of white blood cell) produce antibodies that specifically recognize and destroy an encountered foreign antigen, conferring future protection against that antigen. In passive immunity, blood serum containing these antibodies can be transferred to other animals to confer protection against the target antigen. Previously, it was shown that immunization of hamsters with serumcontaining antibodies against B. burgdorferi prevented infection when the hamsters were challenged with the bacterial strain. Dr. Erol Fikrig pipetting in the lab. PHOTOGRAPHY BY PAUL-ALEXANDER LEJAS However, scientists did not know what specific antigens trigger the production of protective antibodies against Lyme disease. Fikrig and Flavell would have to solve that mystery. In their 1990 paper published in Science, Fikrig and Flavell—along with collaborators Stephen Barthold and Fred Kantor—hypothesized that a possible candidate for the antigen was outer surface protein A (OspA), which is a lipoprotein (a particle composed of fats and proteins), on B. burgdorferi. To test this hypothesis, the gene for OspA in a B. burgdorferi strain was cloned into the bacteria E. coli, such that the E. coli would express OspA. Mice then received either the OspA-transformed bacteria or a control. Four weeks later, an antibody response was detected in mice that received the OspA-transformed bacteria, suggesting that humoral immunity had developed in response to OspA. The team found that the mice that received the OspA-transformed bacteria were successfully protected from infection from B. burgdorferi. While the control mice showed evidence of arthritis, inflamed heart tissue, and infection in blood and spleen cultures, mice that received the OspA-transformed bacteria showed no sign of infection—all signs pointed towards successful immunity. Lastly, the researchers found that the serum of the protected mice conferred similar prevention against infection when injected into new mice, demonstrating effective passive immunization. Studies like this one paved the way for a human vaccine against Lyme disease. Indeed, in the <strong>YSM</strong> article published thirty years ago, which covered a similar study highlighting the potential of the OspA vaccine, the writer was optimistic about the vaccine’s release in 1995. What happened, then, over these three decades? LYMErix and The Revival of The OspA Vaccine According to Fikrig, biopharmaceutical company GlaxoSmithKline signed an agreement with Yale to develop the vaccine. Fikrig and Flavell advised them as they developed a three-dose vaccine for humans, under the name LYMErix. The last phase of clinical trials for the vaccine enrolled over ten thousand patients in endemic areas, and demonstrated that LYMErix was safe and effective in reducing the occurrence of Lyme disease in humans. Following FDA approval, LYMErix was released to the public in 1998. Unfortunately, LYMErix’s success was short-lived. The vaccine was discontinued in 2002, even though it remains FDA-approved. LYMErix’s brief time on the market saw low demand and a potential onslaught of lawsuits alleging the vaccine caused arthritis. “These rumors were circulating that the vaccine was making people sick. There was absolutely no evidence for that, and there still is absolutely no evidence for that,” said Flavell, who is now a Sterling Professor of Immunobiology at Yale. However, the controversy, combined with the lack of interest, was enough for GlaxoSmithKline to remove LYMErix from the general public. There has not been another Lyme disease vaccine for humans since then. However, that may soon change. Major pharmaceutical companies such as Pfizer and Valneva are now interested in developing a new Lyme vaccine. The principle behind how these new vaccines would function is similar to findings from past research. “You need a high titer [concentration] of OspA antibodies to work in both [the old and the new vaccines] . . . they’re fundamentally the same in that regard,” Fikrig said. The new vaccines are now being tested in clinical trials, offering the possibility that a human vaccine for Lyme disease may soon return to the market. www.yalescientific.org December 2023 Yale Scientific Magazine 17
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