SUPPLEMENT ARTICLE

The Lyme Disease Vaccine—A Public Health Perspective Angela K. Shen,1 Paul S. Mead,2 and Charles B. Beard2 1Department of Health and Human Services, National Vaccine Program Office, Washington, DC and 2Bacterial Diseases Branch, Division of Vector-Borne Infectious Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

Lyme disease, which is caused by the spirochetal agent Borrelia burgdoferi, is the most common vector-borne illness in the United States. In 1998, the US Food and Drug Administration approved a recombinant Lyme disease vaccine that was later voluntarily withdrawn from the market by the manufacturer. Current Lyme disease prevention efforts focus on a combination of methods and approaches, including area acaricides, landscape management, host-targeted interventions, management of deer populations, and personal protective measures, such as the use of insect repellant and tick checks. Although these methods are generally safe and relatively inexpensive, the primary limitations of these methods are that their effectiveness has been difficult to demonstrate conclusively and that rates of compliance are generally poor. An effective human Lyme disease vaccine that has been adequately evaluated in the highest-risk population groups could be very beneficial in preventing Lyme disease; however, it would need to meet high standards regarding safety, efficacy, cost, and public acceptance.

Lyme disease is a multi-system illness that, in North America, is caused by Borrelia burgdorferi sensu stricto, which is a spirochete transmitted by Ixodes species ticks. Clinical features of human infection include dermatologic, neurologic, and rheumatologic manifestations [1]. In nature, the spirochete is maintained in a complex cycle in which small mammals and birds serve as reservoirs and in which deer determine vector abundance [2]. Lyme disease ranks among the top 10 notifiable conditions in the United States, on par with the vaccinepreventable diseases varicella and pertusus (Table 1) [3]. In 2009, state and territorial health departments reported 29,959 confirmed and 8,509 probable cases to the Centers for Disease Control and Prevention (CDC) [3]. Geographically, the distribution of Lyme disease cases is highly focal, with 10 states in the Northeast and upper

Correspondence: Charles B. Beard, MD, CDC-DVBID, 3150 Rampart Rd, Fort Collins, CO 80526 ([email protected]). Clinical Infectious Diseases 2011;52(S3):S247–S252 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2011. 1058-4838/2011/52S3-0001$37.00 DOI: 10.1093/cid/ciq115

Midwest accounting for 93% of all reported cases (Figure 1). In counties in which Lyme disease is highly endemic, annual incidence can exceed 250 reported cases per 100,000 population [4]. Case reports have increased over the decade as a result of better ascertainment; nevertheless, there is also evidence of disease expansion in some geographic areas [4–6]. As with other tick-borne diseases, the incidence of Lyme disease has a bimodal distribution with respect to age (Figure 2). Rates are highest among children 5–9 years of age (8.6 cases per 100,000 population) and among adults 55–59 years of age (7.8 cases per 100,000 population). The lowest rate is seen among young adults 20–24 years of age (3.0 cases per 100,000 population). Male patients account for 53% of reported cases [4]. LYME DISEASE VACCINES—A BRIEF HISTORY Two pharmaceutical companies developed vaccines for Lyme disease in the early 1990s, LYMErix (SmithKlineBeecham) and ImuLyme (PasteurMe´rieuxConnaught). Both vaccines were based on the Lyme Disease Vaccine and Public Health

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Table 1. Leading Nationally Notifiable Diseases reported to the US Centers for Disease Control and Prevention, United States, 2009 Rank

Disease

No. of cases

1

Chlamydia

1,244,180

2 3

Gonorrhea Salmonellosis

301,174 49,192

4

Syphilis

44,828

5

Novel influenza A

43,696

6

AIDS

36,870

7

Lyme disease

29,959

8

Varicella

20,480

9

Giardiasis

19,399

10

Pertussis

16,858

NOTE.

Adapted from [3].

B. burgdoferi outer surface protein A (OspA), and both vaccines went forward to phase III clinical trials involving .10,000 participants each. LYMErix was licensed by the US Food and Drug Administration (FDA) on 21 December 1998 for use in individuals 15–70 years of age. It was administered in 3 doses, with the 2 booster doses given at 1 month and 12 months after the primary vaccination. The phase III trial results were favorable and showed a 76% efficacy in preventing laboratory-confirmed Lyme borreliosis and a 100% efficacy in preventing asymptomatic infection in individuals who completed the 3-dose series [7]. Adverse reactions reported in the trial included mild-to-moderate local or systemic reactions lasting a median of 3 days. On the basis of phase III clinical trial data, the CDC’s Advisory Committee on Immunization Practices (ACIP) published

recommendations in June 1999 [8] for use of LYMErix in persons residing, working, or recreating in areas of high or moderate risk, which included the following: (1) Lyme disease vaccination should be considered for persons 15–70 years of age who engage in activities (eg, recreational, property maintenance, occupational, and leisure activities) that result in frequent or prolonged exposure to a tick-infested habitat. (2) Lyme disease vaccination may be considered for persons 15–70 years of age who are exposed to a tick-infested habitat but whose exposure is neither frequent nor prolonged. The benefit of vaccination beyond that provided by basic personal protection and early diagnosis and treatment of infection is uncertain. (3) Lyme disease vaccination is not recommended for persons who have minimal or no exposure to a tick-infested habitat. The ACIP recommendations also issued caveats regarding individuals for whom the vaccine was not recommended, including persons living, working, or recreating in low-risk or no-risk areas; adults .70 years of age; pregnant women; and persons with immunodeficiency, musculoskeletal disease, or a history of Lyme disease. Although considered to be a high risk population, children ,15 years of age who live in areas where Lyme disease is endemic were not recommended to receive vaccination because of a lack of data on safety and immunogenicity in this age group. Vaccination for travelers to high-risk areas was recommended only if frequent or prolonged exposure was anticipated [8]. From December 1998 through July 2000, .1.4 million doses of the vaccine were distributed. According to the Vaccine Adverse Event Reporting System (VAERS), which is a passive surveillance system that monitors vaccine safety

Figure 1. Reported cases of Lyme Disease, United States, 2009. S248

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Figure 2.

Reported cases of Lyme disease, by patient age, United States, 1992–2006.

post-licensure, 905 adverse events were reported during this time period [9]. Of these reports, 7.4% were classified as serious, compared with a 15% average of the 10,000 VAERS reports for all vaccines annually. Under VAERS, a serious event is defined as ‘‘one which resulted in life-threatening illness, hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, or death, or required an intervention to prevent any of these events’’ [9, p. 1604, 10, p. 530]; it does not necessarily imply causation. The majority (56%) of adverse events occurred after the first dose of the vaccine, and the most common adverse events reported included arthralgia, myalgia, pain, asthenia, headache, flu-like symptoms, fever, pain at the site of the injection, rash, and injection site hypersensitivity. Because of concerns at the time regarding the theoretical linkage of the HLA-DR4 major histocompatibility locus to potential adverse events, significant attention was given to vaccine recipients who reported arthritis, rheumatoid arthritis, or athrososis, which included 59, 9, and 34 individuals, respectively. Because the occurrence of arthritis reported as an adverse event among vaccine recipients was considered to be less than that estimated to occur in the background population, the incidence of these events was not viewed as unexpectedly high. In addition, no temporal association was found between vaccine administration and onset of symptoms [9]. Consequently, the CDC and the FDA reported no evidence of unexpected or unusual adverse events associated with LYMErix administration, based on VAERS findings. Despite the favorable results obtained in the phase III trial and the lack of evidence of excess adverse events as reported through VAERS, accounts of patients who had experienced serious vaccine-related complications began to surface in the media and on the internet. These accounts were followed by allegations that many patients with adverse events were not properly reported to VAERS and that physicians in general were poorly educated on

the proper use of the vaccine. These adverse events were publicized broadly, and in December 1999, a class action lawsuit was filed by Sheller, Ludwig, and Bailey [11]. In February 2002, GlaxoSmithKline (formerly SmithKlineBeecham) voluntarily discontinued distribution of LYMErix, citing poor sales, and withdrew their license several years later [12]. A number of perceived factors, however, can be speculated to have contributed to the decision by GlaxoSmithKline. These include the negative publicity linked to unconfirmed adverse events, a looming class action lawsuit, perceived safety concerns resulting in a reduction in public confidence, and what was interpreted by some as a weak public health recommendation for use by the CDC and ACIP [13]. Each of these factors is very important, not only in relationship to the failure of LYMErix, but also to the success of any future human Lyme disease vaccines. LYME DISEASE PREVENTION AND THE POTENTIAL UTILITY OF A SAFE AND EFFECTIVE VACCINE Lyme disease prevention has focused traditionally on reducing human exposure to the bites of infected ticks. Current recommendations include practices such as the following: (1) avoiding tick-infested areas; (2) using insect repellants; (3) wearing light-colored clothing on which ticks are more readily detected; (4) wearing long trousers and tucking them into socks to keep ticks on outer clothing; (5) performing bodily tick checks, followed by prompt tick removal; (6) landscape management; (7) acaricide applications on property or targeted to hosts; and (8) management of deer populations [14]. Although these methods are generally safe and relatively inexpensive, the primary limitations are 2-fold: their effectiveness has been difficult to demonstrate conclusively, and rates of compliance are generally poor [14–17]. Numerous studies have shown that vector tick populations can be reduced by acaricide application or by the use of bait boxes or deer-feeding stations that incorporate acaricidebearing wicks. The large community trials necessary to demonstrate an actual reduction in human disease risk, however, have never been conducted. In addition, there are multiple reasons why individuals may be reluctant to adopt these practices, including cost, inconvenience, and potential safety concerns regarding the use of synthetic chemicals. Under certain circumstances, post-exposure antibiotic prophylaxis may be recommended for preventing Lyme disease. There are reasons, however, why broad scale use of this practice is not advised [18]. Consequently, a safe and effective Lyme disease vaccine could be very beneficial in reducing the incidence of human illness and, in fact, is the only prevention method ever shown to be efficacious in large community trials [19]. Lyme Disease Vaccine and Public Health

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EXPECTATIONS FOR A SUCCESSFUL NEW LYME DISEASE VACCINE Future prospects for a new Lyme disease vaccine depend on understanding and addressing issues at the intersection of science, policy, and public perception. Three key factors compel the call for a Lyme disease vaccine strategy in the United States and other parts of the globe. These include the steady increase in reported cases, the threat of geographic expansion of areas of endemicity, and the insufficiency of current alternative prevention methods. The experience with LYMErix—both for the pharmaceutical industry, which lost millions of dollars, and for some of the public at risk, who felt that the vaccine was not safe—has led to a clearer understanding of factors that can influence the success of a second-generation vaccine. In addition to the general considerations for an ideal vaccine—safety, efficacy, and cost-effectiveness—there are other factors to consider that are unique to the success of a Lyme disease vaccine. These include the following: (1) the mechanism of action; (2) the target population; (3) the existence of other tick-borne disease agents transmitted by the same vector; (4) limited geographic distribution; (5) the relatively low illness severity in the majority of Lyme disease cases, in comparison with the illness severity of other vaccine-preventable diseases; and (6) support from the health care delivery system in the use of a vaccine. An ideal vaccine must be able to induce a high and sustained duration of protection, preferably for a number of years and with the fewest number of booster doses possible (ideally, with no booster doses). LYMErix lacks some of these ideal characteristics owing to its unusual mode of action as a ‘‘transmission blocking’’ vaccine. Because the vaccine-induced protective response occurs in the nymph or adult tick vector when it feeds and before the causative spirochete enters the human host, the vaccine must produce high levels of circulating antibody to ensure protection against infection at the time of a tick bite [19]. ‘‘Breakthrough’’ infections cannot be cleared by host antibodies or trigger an anamnestic response, because B. burgdorferi no longer synthesize OspA at the time of entry into skin. Therefore, although OspA-based vaccines have been shown to be effective, it is unlikely that adequately protective titers can be achieved and maintained without multiple booster vaccinations. If fewer booster doses are important for the success of an ideal Lyme disease vaccine, antigens other than OspA may need to be identified. A second concern about a new candidate Lyme disease vaccine relates to the necessity for the vaccine to be approved for use in the highest-risk groups. As mentioned above, one of the limitations of LYMErix was that, at the time of licensing, it had not yet been approved for use in children ,15 years of age. Consequently, the vaccine was not available for one of the groups at highest risk for contracting Lyme disease, children S250

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5–14 years of age. It is imperative that a second-generation Lyme disease vaccine is demonstrated to be safe and effective in this target population. A third concern for a new Lyme disease vaccine has to do with the potential false sense of security that could result in vaccinated individuals who neglect to consider that the ticks that transmit Lyme disease transmit a number of other pathogens, as well. The black-legged tick Ixodes scapularis is the primary vector of both Babesia microti and Anaplasma phagocytphilum, which are the causal agents of babesiosis and human granulocytic anaplasmosis, respectively. There is a concern that persons who receive a Lyme disease vaccine may not be as vigilant in protecting themselves against tick bites and, therefore, may be at increased risk of acquiring these other pathogens. Consequently, if a second-generation Lyme disease vaccine becomes available, vaccine administration should occur in a context in which vaccine recipients realize that they must continue to employ personal protective measures against ticks to avoid these other disease agents. Two additional considerations in the development of a future Lyme disease vaccine are important to recognize. First, sales for a vaccine will most likely be geographically limited to the Northeastern and Midwestern regions of the United States, because Lyme disease risk is largely regional. Second, Lyme disease, when accurately diagnosed, is generally treatable with antimicrobials. Finally, to achieve commercial success in the Unites States, a Lyme disease vaccine must be broadly supported by key partners in the health care system. These partners include the vaccine industry, patients, providers, patient organizations, payers, and federal and state governments, including advisory bodies to the government, such as the ACIP. Support from these key components of the health care system facilitates development and introduction of new vaccines to address public health needs. Communication, education, and transparency throughout the development and licensure process results in a deeper understanding of the vaccine, especially in the case of a vaccine for Lyme disease, and how its use may be beneficial to the individual and the broader society. This understanding helps to inform attitudes about the vaccine not only among those individuals who are most vulnerable to Lyme disease but also among all of the other stakeholders who share a partnership role in vaccine development, licensing, distribution, and administration. PUBLIC HEALTH’S ROLE IN VACCINE DEVELOPMENT AND SUCCESS Vaccine strategies are important public health tools that are used to address disease incidence, morbidity, and mortality. Vaccines are complex products that are developed through the

contributions of many federal and nonfederal partners. This informal network of partnerships is responsible for supporting research and development that leads to the licensure and use of vaccines. Activities fundamental to this end include epidemiologic studies and surveillance, basic and applied research, development and testing of vaccine candidates, establishment of a manufacturing base, and regulatory oversight. Several US government agencies are charged with ensuring public health investment in these activities and with building strong cross-sector partnerships toward developing vaccines for use [19]. Among the many agencies with a role in vaccine research and development, the CDC, the Department of Defense, the FDA, the National Institutes of Health, and the United States Agency for International Development have the largest investment in vaccine development. These agencies, together with vaccine companies and academia, are central to addressing and tackling the challenges involved in bringing a vaccine to licensure. Successful vaccine development relies on these partnerships and on a common understanding of what is a public health priority. Indications from the public health community, including the government, consumers, health care providers, and vaccine manufacturers, regarding these priorities can be helpful in galvanizing the vaccine enterprise and in driving development and subsequent appropriate use. Although science and technology, public health need, and economic incentives drive development programs, public acceptance of the vaccine and compelling information about its benefits are crucial to success. The public dimension of Lyme disease is complicated [20]. The development, licensure, and voluntary discontinuation of LYMErix highlight the challenges of developing and introducing a novel vaccine to the US market. Although the vaccine was a commercial failure, there were a number of significant achievements and critical lessons learned. The US vaccine and immunization system recognized a disease syndrome, isolated the causative agent, and translated bench science to the bedside over a relatively short period of time. The vaccine was a priority for those individuals and communities most impacted by the disease. Although its safety and efficacy were demonstrated, the vaccine was nonetheless a commercial failure and is no longer available to those in need. The success of a second-generation Lyme disease vaccine will be determined not only by the safety and efficacy of the vaccine but also by the capacity of the multiple public and private sector partners to respond to key lessons learned from the failure of LYMErix. CONCLUSION Since the isolation, identification, and characterization of B. burgdorferi over 20 years ago, much progress has been made

in understanding the complexity of Lyme disease. Currently, no human Lyme disease vaccine is commercially available, and preventive options have key limitations. However, newer insights into the basic biology and molecular genetics of B. burgdorferi are promising and may lead to new vaccine candidates. A future Lyme disease vaccine must not only face conventional scientific and regulatory challenges necessary to achieve licensure but also address heightened public concern to achieve widespread acceptance as an improved vaccine. The key lesson learned from the LYMErix development story is that science and innovation are inadequate, by themselves, to assure that the public health value of a vaccine is realized. The public health community is faced with complex issues that influence vaccine acceptance in a time of unprecedented interest in the development and availability of new vaccines. The experience with LYMErix serves as a clear signal that public interest and acceptance, the initial limitations of the vaccine (including the complex vaccine schedule), and the advocacy groups concerned about vaccine safety in the United States have tremendous influence on the success of a vaccine. With science and public health as focal points driving a future vaccine, coupled with a deep and thorough understanding of the environment necessary to foster understanding and appropriate use of a vaccine strategy, a next-generation vaccine can be realized. A safe and effective Lyme disease vaccine, if produced and accepted, would provide a critical resource in Lyme disease prevention efforts. Acknowledgments We thank Dr. Barbara J. Johnson for her helpful criticism and suggestions. Supplement sponsorship. This article was published as part of a supplement entitled ‘‘The Need for a New Lyme Disease Vaccine Sponsor’’ sponsored by Baxter Laboratories and Centers for Disease Control, Fort Collins, CO, and Stanley Plotkin. Potential conflicts of interest. All authors: no conflicts.

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