Stuart R. Gallant, MD, PhD
In 1991, Helmut and Erika Simon, two German tourists hiking in the Alps near the Austrian/Italian border when they saw a body lodged in the snow and ice. Initially thought to be corpse of a modern-day mountaineer, the body turned out to be much older. “Ötzi,” as he became known, was a neolithic hunter who died and became mummified in an Alpine glacier. (An artist’s conception of what Ötzi looked like in life appears at the top of this post.) Scientific dating has shown that he lived sometime around 3200 BC. Scientific study has revealed much about Ötzi, including the fact that he had contracted Lyme disease at some time during his life [1].
So, Lyme disease has been with humans for millennia; however, it has drawn popular and medical attention only recently. In the early 1980s [2], Willy Burgdorfer reported that a “treponema-like spirochete was detected in and isolated from adult Ixodes scapularis (formerly, Ixodes dammini), the incriminated tick vector of Lyme disease.” For this work, the Lyme bacteria, Borrelia burgdorferi, was named for the naturalized American scientist who worked at the Rocky Mountain Laboratories of the National Institute of Allergy and Infectious Diseases.
Lyme disease cases are quite common in the Northeastern United States today for two reasons: 1) populations of white-footed mice and Eastern chipmunks serve as reservoir hosts for the disease, and reforestation in the northeastern United States has boosted the population of these animals, 2) Americans enjoy getting out in nature for hiking and camping which exposes them to infectious Ixodes scapularis ticks which feed on blood of the mice and chipmunks.
Today’s post is dedicated to Lyme disease vaccines.
Lyme Disease Bacteria
Lyme disease spirochetes can be visualized by microscopy. The figure below is from Willy Burgdorfer’s 1982 Nature publication [2]. As the caption describes, Borrelia burgdorferi bacteria are present in the midgut of infected ticks. They pass the infection to humans when they attach and bite; however, transmission is not very efficient. In one study, the transmission rate was 1% for tick attachments of less than 72 hours and higher for longer attachments [3]. On the right of the figure, spirochetes are seen in the serum of a Lyme disease patient:
Signs and symptoms of infection include: target or bullseye rash and flu-like symptoms (fatigue, headache, body ache, and fever and chills). Without treatment, Lyme disease can disseminate throughout the body, leading to sequelae including joint pain and cognitive impairment. Antibiotic treatment can last from 2 weeks to a month depending on whether localized or disseminated disease is being treated.
Technical Issues in Lyme Disease Vaccination
In considering a Lyme disease vaccine, a significant consideration is who to vaccinate. Vaccination can be an expensive way to prevent disease, particularly if the incidence the disease is low. Meltzer and coworkers did an analysis of the costs of vaccinating against Lyme disease [4]. The study is more than 20 years old, so the precise numbers are not as important as the general conclusion. Their analysis showed a cost of about $4,500 per case of Lyme disease averted, so they suggested that universal vaccination in the Northeast did not make sense economically. In 2000, a report funded by NIH recommended against childhood vaccination against Lyme disease in Lyme endemic areas of the northeastern US [5]. Again, the concern was the relatively high expense of universal vaccination ($100,000 per QALY saved according to the report’s estimate). So, it is important to realize that when vaccination for Lyme disease is being considered, the public health wisdom is to focus on people at risk: folks that spend a lot of time in areas of the Northeast where they are likely to run into ticks carrying Lyme disease (for example, avid hikers, people employed in outdoor occupations in or near the woods, or soldiers and first responders under training in endemic areas).
There are multiple ways to produce a vaccine against Lyme disease. Here are some of the technical considerations:
- Whole Cell Vaccines: One approach to vaccination would be to grow large quantities of Borrelia burgdorferi and kill or inactivate it to make a vaccine [6]. There are some significant limitations to this strategy. Whole cell vaccines produce a diverse group of antibodies binding different epitopes on the bacteria. This broad range of antibodies could throw of diagnostic tests for Borrelia burgdorferi, making it difficult to know if a person who had been vaccinated was infected with Borrelia burgdorferi. Further, because Borrelia speciesvary geographically, vaccination against a single culture of the bacteria could leave the patient vulnerable to infection by variants. Finally, whole cell vaccines may not be the best way to raise long lasting antibody responses.
- Antigen Based Vaccines: One or a small number of Borrelia burgdorferi proteins (i.e., antigens) can be produced and tested for their ability to induce a protective immune response. Some antigens which have been investigated include [6]:
| Antigen | Role in B. burgdorferi | Antibody Response |
| OspA and OspB | Outer surface proteins A and B (OspA and OspB) are essential for survival of the bacteria in the tick midgut. | OspA: effective antibody response. OspB: OspB protein sequence varies between strains; use of a single sequence may allow some species to escape. |
| OspC | Outer surface protein C (OspC): 1) helps B. burgdorgeri invade tick salivary glands and 2) as the bacteria invades a mammalian host, it increases OpsC and decreases OspA and OspB. | Does not produce long term response; is not protective across multiple species. |
| DbpA | Decorin-binding proteins (DBPs) are surface lipoproteins that allow tissue attachment during infection. | Not protective against tick-transmitted infection. |
| Bbk32 | BBk32 is a lipoprotein that inhibits the host complement system. | Effective as an antigen in combination with DbpA and OspC, but not alone. |
- Site of Action: Interestingly, the protective action of certain Lyme disease vaccines (for example, LYMErix from SmithKline Beecham) is not in the blood of the vaccinated patient. In these vaccines, the tick takes a blood meal from the vaccinated person which of course includes antibodies—the antibodies then neutralize the Lyme disease bacteria within the tick’s gut. As noted above, the natural transmission rate of the bacteria from tick to human is quite low (1% for attachments of less than 72 hours), so the small tweak of including human antibodies in the tick’s food tips the transmission rate to an even more miniscule chance. In clinical study of LYMErix, there was a 75% reduction in Lyme disease among the vaccinated subjects, compared with the unvaccinated control subjects.
- Precautions: A secondary benefit of vaccination (in addition to reducing the risk of Lyme disease infection) would be avoidance of the need to wear long pants, tuck pants legs into socks, and take other anti-tick precautions during hiking in the Northeast United States. However, this dream of frolicking in the woods in Bermuda shorts is unrealistic. As mentioned above, vaccination against Lyme does not seem to be 100% effective. (In the case of LYMErix, it was only 75% effective in clinical study.) Also, ticks carry other infections, so a tick can never be seen as a benign passenger when someone goes for a walk in the woods. In other words, precautions will always be needed during a hike in the Northeast (and in other areas with resident tick populations, such as Europe).
Licensed Lyme Disease Vaccines And Ones In Trials
To date, there have been at least four development candidates that reached clinical trials in humans, along with numerous veterinary products:
| Name | Mechanism/ Duration | Stage | Population |
| LYMErix by SmithKline Beecham | Recombinant protein (outer surface protein A (OspA) of B. burgdorferi) with adjuvant. 3 vaccination schedule provided immunity for at least 12 months. | Marketed in US 1998 to 2002. Withdrawn due to poor sales and public controversy [7]. | Human |
| ImuLyme by Connaught Laboratories | Recombinant protein (outer surface protein A (OspA) of B. burgdorferi) without adjuvant | Clinical trials at same time as LYMErix. Withdrawn prior to licensure due to small predicted market demand. | Human |
| VLA15 by Valneva | Six most common outer surface protein A (OspA) serotypes prevalent in North America and Europe | Phase 3 Clinical Trial initiated August 2022. Offers coverage for Lyme disease variants found in Finland, Germany, Netherlands, Poland, Sweden and United States. | Human |
| Lyme PrEP | Monoclonal antibody against outer surface protein A (OspA). Modified to increase antibody half-life; may requires more than 1 injections to cover a single year (i.e., season). Must be given each season. | In clinical trials in 2022. | Human |
| 19ISP mRNA Vaccine | Creates immunity to tick saliva protein, leading to inflammation at bite site, reducing the likelihood of infection. | Early development. | Human |
| crLyme by Vanguard | Outer surface protein A (OspA) combined with 14 different outer surface protein C (OspC) epitopes derived from diverse OspC proteins, 15 months duration. | On veterinary market since 2016; discussions regarding possible human version are ongoing. | Canine (Possible Human Version to Follow) |
| RECOMBITEK Lyme by Boehringer Ingelheim | Lipidated outer surface protein A (OspA), 12 months duration. | On veterinary market based on clinical trial conducted in 2000. | Canine |
| Lymevax by Zoetis | Bivalent whole-cell inactivated bacterin | On veterinary market. | Canine |
| Duramune (truCan) Lyme by Elanco | Bivalent whole-cell inactivated bacterin | On veterinary market. | Canine |
| Nobivac Lyme by | Bivalent whole-cell inactivated bacterin | On veterinary market. | Canine |
All of these vaccines and vaccine candidates raise antibodies against B. burgdorferi, but what antibody levels are required to ensure protection and how long can those levels be maintained following vaccination? With a 0, 1, and 6 month injection schedule of LYMErix, scientists looked at the level of antibody required for prevention of infection versus the level maintained by human subjects [8]:
As would be expected, essentially all of the subjects had protective antibody levels just after completing the course of three jabs. But, only just more than ½ of the subjects had protective levels 12 months after completing the series. For the LYMErix vaccine, the protective antibodies needed to be maintained at a high level in the blood because the antibodies have to travel to the gut of the tick and do their job there. There was no room for the immune system to rev itself up to meet the B. burgdorferi challenge and do its magic in the patient’s blood—if the vaccine was going to do its work as planned. Bottom line: whether you are a dog or a person, the vaccine products against Lyme disease seem to last about 1 year before a new jab is required.
Lessons and Challenges
Vaccine development is a challenge:
- Fortunately, as we learn more about the immune system, developing safe, nonreactive vaccines is becoming easier.
- For a vaccine such as Lyme disease, the market is relatively small. Valneva’s strategy of including 6 different OspA variants makes sense because it allows the product to enter more regions, spreading the cost of development and enhancing the potential market.
- Public perception of vaccines continues to be a challenge. Strong outreach to healthcare providers and potential recipient populations is an important part of the success of a vaccine. Presenting data on vaccination in a clear, compelling, and easy to understand format is a critical part of that outreach.
Whatever the status of Lyme disease vaccines in the future, use of common sense while venturing out of doors is wise. If you plan to venture into the woods during the months when Lyme disease is an issue, you will want to carry out the standard protective measures: 1) wear long pants tucked into your socks, 2) do periodic tick checks during your walk and upon returning home, 3) light colored clothing will help you spot the ticks which are about 1/8 to 1/4 inch in size:
[1] Keller, A., et al. “New insights into the Tyrolean Iceman’s origin and phenotype as inferred by whole-genome sequencing,” Nat Commun 28;3:698 (2012).
[2] Burgdorfer, W., et al. “Lyme Disease—A Tick-Borne Spirochetosis?” Science 216(4552):1317-9 (1982).
[3] Sood, S.K., et al. “Duration of Tick Attachment as a Predictor of the Risk of Lyme Disease in an Area in which Lyme Disease Is Endemic,” J Infect Dis 175(4):996-9 (1997).
[4] Meltzer, M.I., et al. “The Cost Effectiveness of Vaccinating against Lyme Disease,” Emerg Infect Dis 5(3):321-8 (1999).
[5] Stratton, K.R., et al. Vaccines for the 21st Century: A Tool for Decisionmaking, National Academies Press (US) (2000).
[6] Embers, M.E. and Narasimhan, S. “Vaccination Against Lyme Disease: Past, Present, and Future,” Front Cell Infect Microbiol 12;3:6 (2013).
[7] The negative reaction to LYMErix fell into two broad categories: 1) among public health experts, Lyme disease was seen as a treatable malady, and vaccination was seen as excessively expensive compared to the benefit derived by the patient and 2) among patient advocacy groups, rare vaccine side effects were thought to be inadequately accounted for in the design of clinical trials and post-marketing studies. There is an excellent review of the controversy: “The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health,” by R. A. Aronowitz, Milbank Q 90(2):250-77 (2012).
[8] Van Hoecke, C., et al. “Alternative Vaccination Schedules (0, 1, and 6 Months Versus 0, 1, and 12 Months) for a Recombinant OspA Lyme Disease Vaccine,” Clinical Infectious Diseases 28:1260–4 (1999).
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