In November of 1975, in the town of Old Lyme, Connecticut, two mothers observed a strange trend in the community. Their observations, according to Shana Elbaum-Garfinkle’s article, “Close to Home: A History of Yale and Lyme Disease,” contributed to the discovery of the tick-borne disease that affects the lives of thousands of people living in rural areas. The mothers noticed that, like their own children, many other children in town were diagnosed with juvenile rheumatoid arthritis. However, the doctors were unable to explain what caused the children to develop this joint disease and, therefore, the children remained untreated. In seeking to understand this mysterious disease, the two mothers reached out to a research team at the Yale School of Medicine.

The research team at Yale, led by Allan C. Steere and Stephen E. Malawista, conducted an investigation in Old Lyme and two other towns near the eastern coast of Connecticut. They interviewed families of children who developed rheumatoid arthritis, and learned that all the children displayed rashes prior to the signs of arthritis. In addition, many of the children reported spotting ticks on their skin at the end of the day. Piecing together the clues, Steere and Malawista unveiled the mysterious disease, which was named Lyme disease after the town where these children lived. They determined that this disease was caused by a bacterium called Borrelia burgdorferi which lived in the gut of Ixodes scapularis ticks – the creatures that had bitten the children.

Lyme disease is caused by the transmission of infectious bacterium through Ixodes ticks during feeding. While the children in Old Lyme were outside playing in the woods, ticks hiding in the grassy area may have attached to the children’s skin. As the tick sucks in blood from its host, the burgdorferi bacteria in the form of spirochetes (spiral-shaped bacteria) begin to multiply in the tick’s midgut. Eventually the bacteria pass into the tick’s circulatory system and travel to the salivary gland. From there, the microbes are transmitted into the child’s body through the tick’s saliva.

Once a victim is infected with Lyme disease, he or she can be easily treated with antibiotics. According to the Centers for Disease Control and Prevention (CDC), antibiotic treatments are separated into two types: oral and intravenous. Generally, patients are treated orally with antibiotics such as doxycycline and amoxicillin. Patients who develop neurological or cardiac problems are treated intravenously with antibiotics such as penicillin and ceftriaxone. A few weeks after receiving antibiotic treatment, most of the patients will recover fully. Hence, the Infectious Diseases Society of America (IDSA) describes Lyme disease as something “hard to catch and easy to cure.” However, the statistics on Lyme disease display a very different picture. Since the 1990’s, cases of Lyme disease have increased ten-fold. In 2013, the CDC reported that 300,000 cases of Lyme disease were diagnosed annually in the United States and approximately 65,000 to 85,000 cases diagnosed per year in Europe. But, if Lyme disease is so easy to cure, then why is it becoming more prevalent over the years?

Fred Kantor, a professor of medicine at Yale University and the author of the 1994 Scientific American article, “Disarming Lyme Disease,” shares his theory concerning this phenomenon. Kantor proposes that the problem with Lyme disease lies in the difficulty with diagnosing it during its early phases. This is due to the disease’s wide range of symptoms and the unreliability of diagnostic techniques. When a person is first infected with the bacterium, he or she can develop a broad spectrum of symptoms. Most patients, like the children in Old Lyme, will develop a rash that resembles a “bull’s eye” around the area of the tick bite. Many will also develop flu-like symptoms such as fever, headaches and chills. Patients in Europe have also been observed with neurological problems such as meningitis and radiculoneuropathy (an infection at the roots of the spinal nerve) prior to the diagnosis of Lyme disease.

Since Lyme disease shares many of its symptoms with other illnesses and its symptoms vary across patients, it is often misdiagnosed. In some cases, patients do not develop the characteristic “bull’s-eye” rash after the infection. Under such circumstances, doctors struggle to confirm the existence of Lyme disease. Delayed diagnosis, however, allows for the progression of the disease with potentially severe consequences, as in the cases of the children with juvenile rheumatoid arthritis and the case with Stanley Plotkin’s son. Stanley Plotkin, a physician and scientist who helped develop the rubella vaccine, described in a New York Times article, “Bring Back the Lyme Vaccine,” an incident where his son almost died due to delayed diagnosis of Lyme disease.

On a beautiful morning in the suburbs of Philadelphia, Plotkin’s son, Alec, was walking his dog when he suddenly collapsed on the street. When he was brought to the hospital, the physician quickly recognized that Alec was having a cardiac problem due to Lyme disease. Fortunately, Alec was saved after the installation of a pacemaker and treatment with antibiotics. Nevertheless, the cardiac complication could have led to Alec’s death. In fact, Alec had seen a rash on his skin days prior to his collapse. Immediately, he visited the doctor. Yet, since the rash was not in the “bull’s-eye” shape, the doctor quickly dismissed the possibility of Lyme disease. Consequently, Alec’s disease worsened and caused his cardiac problem.

In addition to the broad range of symptoms that complicates the diagnosis of Lyme disease, the unreliability of diagnostic exams also contributes to delayed diagnosis. Although a blood test and laboratory exams exist to help with the diagnosis, they are inaccurate in the early phases of Lyme disease. The exams confirm the existence of Lyme disease by identifying the antibodies against the bacterium. However, according to Kantor, the antibodies do not develop until weeks or even months after an infection. At that point, the disease may have already progressed into its later stages where severe symptoms arise.

As Lyme disease progresses, it can lead to other serious conditions such as chronic arthritis, meningitis, and encephalitis (inflammation of the brain which results in memory loss, mood changes, severe headaches and confusion). Although the disease does not directly cause death, neurological, cardiac and musculoskeletal complications greatly impact the life of patients. A patient may walk down the street one day and, like Alec, collapse onto the ground, waiting for someone to notice him in order to save his life. Or, they may be like the children in Old Lyme with juvenile arthritis. The persistent joint pain prevents the children from running around and enjoying the fun they should be having at their age. Perhaps, for the children in Old Lyme who witnessed the pain their friends suffered through and those living in rural areas and have heard of the incident, the most frightening aspect of Lyme disease is the possibility that they can be bitten by an infectious tick any day just by playing outside. Nonetheless, this fear can be prevented. Scientists are working to bring back the vaccines that will provide first-line defense against the potentially disabling disease.

As early as the late 1980’s, scientists started exploring the idea of creating a vaccine against Lyme disease. In one of his studies, Kantor investigated people near Montauk, N.Y. He learned that the people there were often infected with Montauk knee, a sign of Lyme disease. The condition involved the swelling of one knee, swelling that would subside after a few weeks. More importantly, the condition never returned after the first infection. This led Kantor and his team of scientists to believe that the immune system was capable of developing antibodies against Borrelia antigens, and hence encouraged them to proceed further with their research.

Kantor and his team then conducted multiple studies looking at the surface proteins on the burgdorferi bacterium. The surface proteins are specific to each antigen (a foreign substance – a bacterium in this case – that induces the production of antibodies in the human body). The antibodies bind to the surface proteins and signal the body’s immune system to destroy the bound antigen. As the body eliminates the foreign substance, its memory cells memorize the antigen so that the immune system can react more quickly the next time the antigen enters the body, thereby creating immunity against the disease. To accomplish this for Lyme disease, scientists searched for a surface protein that would most effectively induce an immune response against the burgdorferi bacterium.

In 1989, Alan G. Barbour, who conducted similar studies at the University of Texas Health Science Center, identified the OspA protein (outer surface protein A). A vaccine created from the OspA protein was tested on mice that were then exposed to burgdorferi spirochetes. The results showed no sign of infection in these mice, which suggested that the vaccine created from the OspA protein was effective in protecting the human body from the burgdorferi bacterium. After several more animal experiments and clinical trials on 200,000 people, a pharmaceutical company named GlaxoSmithKline introduced the first Lyme vaccine, LYMErix, into the market in 1998. As described by Bogumila Skotarczak in the article, “Why is There Still no Human Vaccine Against Lyme Borreliosis?” the vaccine consisted of the recombinant OspA protein which produced long-term protective response against the burgdorferi microbe. Despite this, GlaxoSmithKline withdrew LYMErix from the market five years later due to its limited efficacy, the lack of a trial on children, and, most importantly, concerns about its side effects. The LYMErix vaccine was for people between the ages of 15 and 70. However, many of the victims of Lyme disease were children under the age of 15. In fact, the child whose mother reported the cases of arthritis in Old Lyme was nine years old at the time. Therefore, the vaccine failed to serve one of the main groups of people in need of it. In addition, the vaccine did not provide 100% immunity against Lyme disease. The vaccine came in three doses, and people had to take all three doses to obtain an efficacy rate of 80%. This meant that 20% of the people who were vaccinated with LYMErix were still at risk of contracting the disease. However, this was not known to the public. So when people who received the vaccine developed signs of arthritis afterwards, they began questioning the safety of the vaccine. Many volunteers vaccinated with LYMErix after its release into the market reported neurological and musculoskeletal side effects like the symptoms seen in Lyme disease patients. A lawsuit was thus filed against the company. Although the case concluded with insufficient evidence supporting the linkage between the musculoskeletal disorder and the vaccine, the public had lost trust and interest in the vaccine. The demand for LYMErix plummeted, and the company withdrew it from the market. While scientists continue to search for a vaccine that is safer and more effective, so far, they have not been successful.

One reason for the failure is the cleverness of the microorganism. Skotarczak reveals that the burgdorferi bacterium adopts different strategies to survive in the human body long enough to cause an infection. The bacterium interchanges within its three developmental forms (spherical, L, and vesicular), which prevents effective treatments from antibiotics. The outer surface protein on the bacterium is also capable of changing forms. The immune system may not be quick enough to develop antibodies to the new form of antigen to prevent its infection. The bacterium also hides inside the host’s own cells such as lymphocytes and macrophages to avoid the attack of the host’s immune system. Since these cells are involved in the destruction of external pathogens and other infected cells, they may not realize that antigens are hiding within them and thus will not attack themselves.

The variability in the species of Borrelia and their surface proteins is another factor delaying the production of a vaccine against Lyme disease. As reported in “A New Approach to a Lyme Disease Vaccine,” as of 2011, there were thirteen documented species of Borrelia in the world. The OspA protein on each of these species is different in its structure. This variability implies that, for the human body to be protected against all thirteen species of Borrelia, it has to produce different antibodies for the OspA protein associated with each of these species. Luckily, only one of those species, the B. burgdorferi, is responsible for causing Lyme disease in the United States. On the other hand, this also means that LYMErix can only protect against Lyme disease caused by this specific species. In order to develop a universal vaccine, scientists today are experimenting with recombinant OspA proteins—proteins that contain OspA regions from different species of Borrelia.

A team of researchers led by Ian Livey of the Department of Medicine at Stony Brook embarked on this task, creating a vaccine that protects against two different species of Borrelia. Ian Livey and his team created a recombinant OspA-based vaccine (rOspA 1/2) from the OspA 1 and OspA 2 serotypes. The OspA 1 serotype is a surface protein on the B. burgdorferi strain while the OspA 2 serotype is found on the B. afzelii strain. The team extracted segments from both the OspA 1 serotype and the OspA 2 serotype and recombined them to form a single recombinant protein. The team then tested the recombinant vaccine on mice. They introduced the burgdorferi bacterium into one group of mice through needle injection and the afzelii bacterium into another group of mice through exposure to feral ticks. Some of the infected mice were treated as controls; they were given aluminum buffer instead of the vaccine. All of the control mice displayed signs of infection following the injection of the bacteria. However, mice that were treated with rOspA 1/2 were 100% immune to the burgdorferi bacterium. Among the group of mice that were challenged with ticks containing B.afzelii bacterium, only three out of 32 mice were infected. The results demonstrated that the rOspA 1/2 vaccine was effective in protecting against both burgdorferi and afzelii strains. More importantly, this experiment confirmed the possibility that immunity against other species of Borrelia can be induced through engineering a protein that contains regions from additional OspA serotypes.

Three years later, in 2014, another lab team led by Par Comstedt proceeded a step closer to developing a safer and universal Lyme borreliosis vaccine. The team created an OspA-based vaccine by recombining regions from three different serotypes of the OspA protein. These regions were on the C-terminal (a region at the end of an amino acid chain) of the protein. Previous studies had shown that the protection against Lyme disease from OspA vaccine occurs when the antibodies bind to epitopes (sites on an antigen where the antibodies attach) in the C-terminal region of the surface protein. This earlier finding suggested that the team only needed to preserve the C-terminal part of OspA for an effective vaccine. Therefore, they removed 45% of the other ineffective parts from the OspA protein, thereby reducing the size of the antigen and its attendant risk. A decrease in the size of the antigen leads to the reduction of the toxicity of the vaccine that contains this antigen. However, when the length of the protein decreases, its stability also decreases; the protein becomes easily degradable under changing temperatures. To preserve immunity against Lyme disease, the C-terminal region must be preserved under extreme temperatures. To resolve this issue, Comstedt introduced a mutation into the bacterium that preserves the structure of the epitopes in the C-terminal, enabling the antibody to bind to the epitopes under varying temperatures.

In addition to reducing the size of the OspA antigen, Comstedt and his team also created a vaccine that protects against three different species of Borrelia. They took two molecules from each of the six OspA serotypes and combined each set of molecules with molecules from a different serotype. The resulting heterodimers (proteins composed of two different polypeptide chains) contained C-terminals from the OspA protein on the different species of the bacteria. The vaccine containing those heterodimers should then be able to protect against multiple strains of Borrelia. When the researchers tested the vaccine on mice injected with B. burgdorferi (OspA serotype 1) and mice challenged with feral ticks containing B. afzelii (OspA serotype 2) and B. garinii (OspA serotype 3), they discovered that the mice were protected from all three strains. Even though this study has only been successfully performed on mice, it confirms the possibility of producing a vaccine that is safer, thermally stable, and effective against a wide range of the Borrelia species.

The studies done by the research teams led by Ian Livey and Par Comstedt establish a framework for the development of a global vaccine against all the different strains of Borrelia. Continuing efforts to analyze different variants of OspA antigen will aid in the progress of this task. Additional studies have also been investigating the development of a vaccine that is 100% protective against Lyme disease with minimal side effects. These combined efforts may finally contribute to a vaccine against Lyme disease in the near future. That vaccine will be safer, more effective and more efficient than LYMErix. When it becomes generally available, children and adults in Old Lyme or in any other wooded and grassy environment will no longer have to worry about the risk of contracting Lyme disease.

References

Comstedt, Pär et al. “Design and Development of a Novel Vaccine for Protection against Lyme Borreliosis.” PLOS ONE 9.11 (2014): n. pag. PubMed Central. Web. 1 Nov. 2016.

Elbaum-Garfinkle, Shana. “Close to Home: A History of Yale and Lyme Disease.” The Yale Journal of Biology and Medicine 84.2 (2011): 103–108. Print.

Kantor, Fred S. “Disarming Lyme Disease.” Scientific American 271.3 (1994): 34. Print.

Livey, Ian et al. “A New Approach to a Lyme Disease Vaccine.” Clinical Infectious Diseases 52.suppl 3 (2011): s266–s270. Web.

Plotkin, Stanley A. “Bring Back the Lyme Vaccine.” The New York Times 18 Sept. 2013. NYTimes.com. Web. 15 Nov. 2016.

—. “Need for a New Lyme Disease Vaccine.” New England Journal of Medicine 375.10 (2016): 911–913. Taylor and Francis+NEJM. Web.

Revkin, Andrew C. “First Shot Is Fired In Lyme Disease War.” The New York Times 24 Jan. 1999. NYTimes.com. Web. 15 Nov. 2016.

Skotarczak, Bogumiła. “Why Is There Still No Human Vaccine Against Lyme Borreliosis?” Folia Biologica 63.3 (2015): 159–165. Print.

“Treatment | Lyme Disease | CDC.” N.p., n.d. Web. 17 Nov. 2016

 

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