Single-domain antibodies reveal unique borrelicidal epitopes on the Lyme disease vaccine antigen, outer surface protein A (OspA).

Camelid-derived, single-domain antibodies (VHHs) have proven to be extremely powerful tools in defining the antigenic landscape of immunologically heterogeneous surface proteins. In this report, we generated a phage-displayed VHH library directed against the candidate Lyme disease vaccine antigen, outer surface protein A (OspA). Two alpacas were immunized with recombinant OspA serotype 1 from Borrelia burgdorferi sensu stricto strain B31, in combination with the canine vaccine RECOMBITEK Lyme containing lipidated OspA. The phage library was subjected to two rounds of affinity enrichment ("panning") against recombinant OspA, yielding 21 unique VHHs within two epitope bins, as determined through competition enzyme linked immunosorbent assays (ELISAs) with a panel of OspA-specific human monoclonal antibodies. Epitope refinement was conducted by hydrogen exchange-mass spectrometry. Six of the monovalent VHHs were expressed as human IgG1-Fc fusion proteins and shown to have functional properties associated with protective human monoclonal antibodies, including B. burgdorferi agglutination, outer membrane damage, and complement-dependent borreliacidal activity. The VHHs displayed unique reactivity profiles with the seven OspA serotypes associated with B. burgdorferi genospecies in the United States and Europe consistent with there being unique epitopes across OspA serotypes that should be considered when designing and evaluating multivalent Lyme disease vaccines.

Lyme disease vaccine attitudes and intentions among parents of children aged 5-18 years in the United States.

BACKGROUND: Lyme disease (LD) is the most common vector-borne disease in the United States, with increasing incidence and geographic range. Case incidence peaks among school-aged children. New LD preventives are in clinical trials. METHODS: We conducted an online survey of parents of children aged 5-18 years in states with high or emerging incidence of LD. Our primary outcome was willingness ("definitely" or "probably") for their child to receive an LD vaccine. Our secondary outcome was preference for annual monoclonal antibody injections compared to a 3-dose vaccine series with boosters. Analyses were weighted to reflect parent gender, parent race/ethnicity, and child age by state. RESULTS: Among 1,351 parent respondents, most (68.0 %) would have their child vaccinated against LD, with significantly more being willing in high compared to emerging incidence states (70.4 % versus 63.6 %, p = 0.027). Of parents who were unsure or unwilling, 33.5 % and 16.5 %, respectively, would do so with a provider recommendation. Vaccine safety concerns were among the top reasons for LD vaccine hesitancy. More parents preferred a pre-formed antibody (42.3 %) compared to a 3-dose vaccine series (34.7 %). Significant predictors of willingness to have one's child vaccinated were higher parental education; higher perceived risk of child getting LD; child spending time outdoors daily or weekly; following a regular vaccine schedule; and positive attitude towards vaccines. Significant predictors of preference for monoclonal antibody over a 3-dose vaccine series included prior awareness of LD, living in a rural area, and less positive attitudes towards vaccines. CONCLUSIONS: Two-thirds of parents in high and emerging incidence states would vaccinate their children against Lyme disease. Addressing safety concerns will be important, and a health care provider recommendation could also encourage those who are unsure or unwilling. Given the slight preference for monoclonal antibody over vaccine, particularly in rural areas, access to both may increase LD prevention.

Biophysical and biochemical characterization of a recombinant Lyme disease vaccine antigen, CspZ-YA.

Lyme disease, caused by Lyme Borrelia spirochetes, is the most common vector-borne illness in the United States. Despite its global significance, with an estimated 14.5 % seroprevalence, there is currently no licensed vaccine. Previously, we demonstrated that CspZ-YA protein conferred protection against Lyme Borrelia infection, making it a promising vaccine candidate. However, such a protein was tagged with hexahistidine, and thus not preferred for vaccine development; furthermore, the formulation to stabilize the protein was understudied. In this work, we developed a two-step purification process for tag-free E. coli-expressed recombinant CspZ-YA. We further utilized various bioassays to analyze the protein and determine the suitable buffer system for long-term storage and formulation as a vaccine immunogen. The results indicated that a buffer with a pH between 6.5 and 8.5 stabilized CspZ-YA by reducing its surface hydrophobicity and colloidal interactions. Additionally, low pH values induced a change in local spatial conformation and resulted in a decrease in α-helix content. Lastly, an optimal salinity of 22-400 mM at pH 7.5 was found to be important for its stability. Collectively, this study provides a fundamental biochemical and biophysical understanding and insights into the ideal stabilizing conditions to produce CspZ-YA recombinant protein for use in vaccine formulation and development.

Background incidence rates of health outcomes in populations at risk for Lyme disease using US administrative claims data.

BACKGROUND: Background incidence rates (IRs) of health outcomes in Lyme disease endemic regions are useful to contextualize events reported during Lyme disease vaccine clinical trials or post-marketing. The objective of this study was to estimate and compare IRs of health outcomes in Lyme disease endemic versus non-endemic regions in the US during pre-COVID and COVID era timeframes. METHODS: IQVIA PharMetrics® Plus commercial claims database was used to estimate IRs of 64 outcomes relevant to vaccine safety monitoring in the US during January 1, 2017-December 31, 2019 and January 1, 2020-December 31, 2021. Analyses included all individuals aged ≥ 2 years with ≥ 1 year of continuous enrollment. Outcomes were defined by International Classification of Diseases Clinical Modification, 10th Revision (ICD-10-CM) diagnosis codes. IRs and 95 % confidence intervals (CIs) were calculated for each outcome and compared between endemic vs. non-endemic regions, and pre-COVID vs. COVID era using IR ratios (IRR). RESULTS: The study population included 8.7 million (M) in endemic and 27.8 M in non-endemic regions. Mean age and sex were similar in endemic and non-endemic regions. In both study periods, the IRs were statistically higher in endemic regions for anaphylaxis, meningoencephalitis, myocarditis/pericarditis, and rash (including erythema migrans) as compared with non-endemic regions. Conversely, significantly lower IRs were observed in endemic regions for acute kidney injury, disseminated intravascular coagulation, heart failure, myelitis, myopathies, and systemic lupus erythematosus in both study periods. Most outcomes were statistically less frequent during the COVID-era. CONCLUSION: This study identified potential differences between Lyme endemic and non-endemic regions of the US in background IRs of health conditions during pre-COVID and COVID era timeframes to inform Lyme disease vaccine safety monitoring. These regional and temporal differences in background IRs should be considered when contextualizing possible safety signals in clinical trials and post-marketing of a vaccine targeted at Lyme disease prevention.

Structural Elucidation of a Protective B Cell Epitope on Outer Surface Protein C (OspC) of the Lyme Disease Spirochete, Borreliella burgdorferi.

Outer surface protein C (OspC) plays a pivotal role in mediating tick-to-host transmission and infectivity of the Lyme disease spirochete, Borreliella burgdorferi. OspC is a helical-rich homodimer that interacts with tick salivary proteins, as well as components of the mammalian immune system. Several decades ago, it was shown that the OspC-specific monoclonal antibody, B5, was able to passively protect mice from experimental tick-transmitted infection by B. burgdorferi strain B31. However, B5's epitope has never been elucidated, despite widespread interest in OspC as a possible Lyme disease vaccine antigen. Here, we report the crystal structure of B5 antigen-binding fragments (Fabs) in complex with recombinant OspC type A (OspCA). Each OspC monomer within the homodimer was bound by a single B5 Fab in a side-on orientation, with contact points along OspC's α-helix 1 and α-helix 6, as well as interactions with the loop between α-helices 5 and 6. In addition, B5's complementarity-determining region (CDR) H3 bridged the OspC-OspC' homodimer interface, revealing the quaternary nature of the protective epitope. To provide insight into the molecular basis of B5 serotype specificity, we solved the crystal structures of recombinant OspC types B and K and compared them to OspCA. This study represents the first structure of a protective B cell epitope on OspC and will aid in the rational design of OspC-based vaccines and therapeutics for Lyme disease. IMPORTANCE The spirochete Borreliella burgdorferi is a causative agent of Lyme disease, the most common tickborne disease in the United States. The spirochete is transmitted to humans during the course of a tick taking a bloodmeal. After B. burgdorferi is deposited into the skin of a human host, it replicates locally and spreads systemically, often resulting in clinical manifestations involving the central nervous system, joints, and/or heart. Antibodies directed against B. burgdorferi's outer surface protein C (OspC) are known to block tick-to-host transmission, as well as dissemination of the spirochete within a mammalian host. In this report, we reveal the first atomic structure of one such antibody in complex with OspC. Our results have implications for the design of a Lyme disease vaccine capable of interfering with multiple stages in B. burgdorferi infection.

Use of the Western blot technique to identify the immunogenic proteins of Borrelia burgdorferi for developing a Lyme disease vaccine.

BACKGROUND: Lyme disease is a serious infectious disease having a restricted worldwide distribution for which there is no vaccine available for human use. OBJECTIVE: This study was designed to determine common reactive antigens involved in Borrelia burgdorferi (Bb) infection that are recognized in mammalian sera that may be useful for vaccine development. METHODS: Blood samples were collected from patients with documented Lyme disease, and from rabbits and mice experimentally infected with either tick-transmitted or culture-grown Borrelia burgdorferi. All samples were then processed for sera. For performing the Western blots, sonicated Bb organisms (whole cell lysates) and protein ladders were separated by protein gel electrophoresis. Immune reactivities of the electrophoresed proteins with the serum samples were then probed with anti-HRP IgG reagent. RESULTS: Rabbit, mouse and human sera consistently reacted with the 41 kDa band of Bb which corresponded to the flagellin protein - the major protein component of this organism's periplasmic flagella, also known as axial filaments or fibrils. Various other Bb antigens of wide molecular weight ranges were also recognized by rabbit and human sera, and less frequently with mouse sera. CONCLUSION: The strong immune response to the 41 kDa flagellin protein by the different mammalian species suggests the utility of a possible vaccine targeting this protein, although other proteins may also be appropriate, for preventing Lyme disease following a bite from an infected tick.

The major epidemiologic, microbiologic, immunologic, and clinical aspects of Lyme disease that form the basis for a newly developed vaccine that may become available soon for human use.

Working together, two major pharmaceutical companies have developed a Lyme disease vaccine consisting of recombinant-derived outer surface protein A (OspA) of the etiologic agent Borrelia burgdorferi. Multiple clinical trials have shown the vaccine to have good safety and efficacy results, and it is hoped that it would become available for human use at least by the year 2025 after receiving approval from the U.S. Food and Drug Administration. There are still challenges left to ensure that the vaccine has, at most, minimal side effects. Also, because the previously developed Lyme disease vaccine was discontinued in 2002 after four years of distribution, due in part, for frivolous reasons having little or no scientific basis, that even led to legal entanglements involving the vaccine manufacturer and some of the medical personnel overseeing the clinical trials, there will be concerns that this newly developed one could be subject again to some of the same unnecessary scrutiny rendering its implementation suboptimal. Initially this review will focus on the key epidemiological, microbiologic, immunologic and clinical aspects of Lyme disease that provide the foundation for developing this type of vaccine that could have a serious impact on the prevalence of this and even certain other tick-transmitted infections.

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA.

The Lyme disease (LD) vaccine formerly approved for use in the United States consisted of recombinant outer surface protein A (OspA) from Borrelia burgdorferi sensu stricto (ss), the bacterial genospecies responsible for the vast majority of LD in North America. OspA is an ∼30 kDa lipoprotein made up of 21 antiparallel ß-strands and a C-terminal α-helix. In clinical trials, protection against LD following vaccination correlated with serum antibody titers against a single epitope near the C-terminus of OspA, as defined by the mouse monoclonal antibody (MAb), LA-2. However, the breadth of the human antibody response to OspA following vaccination remains undefined even as next-generation multivalent OspA-based vaccines are under development. In this report, we employed hydrogen exchange-mass spectrometry (HX-MS) to localize the epitopes recognized by a unique panel of OspA human MAbs, including four shown to passively protect mice against experimental B. burgdorferi infection and one isolated from a patient with antibiotic refractory Lyme arthritis. The epitopes grouped into three spatially distinct bins that, together, encompass more than half the surface-exposed area of OspA. The bins corresponded to OspA ß-strands 8-10 (bin 1), 11-13 (bin 2), and 16-20 plus the C-terminal α-helix (bin 3). Bin 3 was further divided into sub-bins relative to LA-2's epitope. MAbs with complement-dependent borreliacidal activity, as well as B. burgdorferi transmission-blocking activity in the mouse model were found within each bin. Therefore, the resulting B cell epitope map encompasses functionally important targets on OspA that likely contribute to immunity to B. burgdorferi.

Agglutination of Borreliella burgdorferi by Transmission-Blocking OspA Monoclonal Antibodies and Monovalent Fab Fragments.

Lyme disease vaccines based on recombinant Outer surface protein A (OspA) elicit protective antibodies that interfere with tick-to-host transmission of the disease-causing spirochete Borreliella burgdorferi. Another hallmark of OspA antisera and certain OspA monoclonal antibodies (MAbs) is their capacity to induce B. burgdorferi agglutination in vitro, a phenomenon first reported more than 30 years ago but never studied in molecular detail. In this report, we demonstrate that transmission-blocking OspA MAbs, individually and in combination, promote dose-dependent and epitope-specific agglutination of B. burgdorferi. Agglutination occurred within minutes and persisted for hours. Spirochetes in the core of the aggregates exhibited evidence of outer membrane (OM) stress, revealed by propidium iodide uptake. The most potent agglutinator was the mouse MAb LA-2, which targets the OspA C terminus (ß-strands 18 to 20). Human MAb 319-44, which also targets the OspA C terminus (ß-strand 20), and 857-2, which targets the OspA central ß-sheet (strands 8 to 10), were less potent agglutinators, while MAb 221-7, which targets ß-strands 10 to 11, had little to no measurable agglutinating activity, even though its affinity for OspA exceeded that of LA-2. Remarkably, monovalent Fab fragments derived from LA-2, and to a lesser degree 319-44, retained the capacity to induce B. burgdorferi aggregation and OM stress, a particularly intriguing observation considering that "LA-2-like" Fabs have been shown to experimentally entrap B. burgdorferi within infected ticks and prevent transmission during feeding to a mammalian host. It is therefore tempting to speculate that B. burgdorferi aggregation triggered by OspA-specific antibodies in vitro may in fact reflect an important biological activity in vivo.

Past, present, and future of Lyme disease vaccines: antigen engineering approaches and mechanistic insights.

INTRODUCTION: Transmitted by ticks, Lyme disease is the most common vector-borne disease in the Northern hemisphere. Despite the geographical expansion of human Lyme disease cases, no effective preventive strategies are currently available. Developing an efficacious and safe vaccine is therefore urgently needed. Efforts have previously been taken to identify vaccine targets in the causative pathogen (Borrelia burgdorferi sensu lato) and arthropod vector (Ixodes spp.). However, progress was impeded due to a lack of consumer confidence caused by the myth of undesired off-target responses, low immune responses, a limited breadth of immune reactivity, as well as by the complexities of the vaccine process development. AREA COVERED: In this review, we summarize the antigen engineering approaches that have been applied to overcome those challenges and the underlying mechanisms that can be exploited to improve both safety and efficacy of future Lyme disease vaccines. EXPERT OPINION: Over the past two decades, several new genetically redesigned Lyme disease vaccine candidates have shown success in both preclinical and clinical settings and built a solid foundation for further development. These studies have greatly informed the protective mechanisms of reducing Lyme disease burdens and ending the endemic of this disease.

Evaluating public acceptability of a potential Lyme disease vaccine using a population-based, cross-sectional survey in high incidence areas of the United States.

BACKGROUND: Lyme disease incidence is increasing, despite current prevention options. New Lyme disease vaccine candidates are in development, however, investigation of the acceptability of a Lyme disease vaccine among potential consumers is needed prior to any vaccine coming to market. We conducted a population-based, cross-sectional study to estimate willingness to receive a potential Lyme disease vaccine and factors associated with willingness. METHODS: The web-based survey was administered to a random sample of Connecticut, Maryland, Minnesota, and New York residents June-July 2018. Survey-weighted descriptive statistics were conducted to estimate the proportion willing to receive a potential Lyme disease vaccine. Multivariable multinomial logistic regression models were used to quantify the association of sociodemographic characteristics and Lyme disease vaccine attitudes with willingness to be vaccinated. RESULTS: Surveys were completed by 3313 respondents (6% response rate). We estimated that 64% of residents were willing to receive a Lyme disease vaccine, while 30% were uncertain and 7% were unwilling. Compared to those who were willing, those who were uncertain were more likely to be parents, adults 45-65 years old, non-White, have less than a bachelor's degree, or have safety concerns about a potential Lyme disease vaccine. Those who were unwilling were also more likely to be non-White, have less than a bachelor's degree, or have safety concerns about a potential Lyme disease vaccine. In addition, the unwilling had low confidence in vaccines in general, had low perceived risk of contracting Lyme disease, and said they would not be influenced by a positive recommendation from a healthcare provider. DISCUSSION: Overall, willingness to receive a Lyme disease vaccine was high. Effective communication by clinicians regarding safety and other vaccine parameters to those groups who are uncertain will be critical for increasing vaccine uptake and reducing Lyme disease incidence.

A brief history of OspA vaccines including their impact on diagnostic testing for Lyme disease.

The only United States Food and Drug Administration approved vaccine preparation to prevent Lyme disease consisted of a single recombinant outer surface protein A (OspA), which was marketed for use from late 1998 until early 2002, with no vaccine currently available for humans for nearly 20 years. OspA vaccines generate an antibody-mediated, transmission blocking immunity, that prevents Borrelia burgdorferi from being transmitted during a tick bite. Although this OspA vaccine was safe and effective, it likely would have required booster doses to maintain immunity, and vaccination regularly caused false positive results on first-tier serologic testing for Lyme disease, when a whole cell-based enzyme immunoassay was used. Clinical trials are in progress to test a new multivalent OspA vaccine designed to prevent Lyme disease in both the United States and Europe.

Understanding consumer and clinician perceptions of a potential Lyme disease vaccine.

Each year, over 450 000 Lyme disease diagnoses are estimated to occur in the United States, and current preventive measures have been insufficient to stem the rising incidence. An effective human Lyme disease vaccine could be a powerful intervention for population-level impact. In advance of new Lyme disease vaccines coming to market, this study explored barriers to acceptability and motivations for the uptake of a new Lyme disease vaccine. Researchers conducted 9 online focus groups among consumers who may potentially benefit from the vaccine and 30 in-depth interviews among clinician groups who may provide the vaccine. All participants were recruited from three US regions of high Lyme disease incidence. Researchers found that participants shared common motivators to either recommend (clinicians) or accept (consumers) a Lyme disease vaccine, largely driven by perceived benefits of the vaccine, the lack of current effective preventive measures and a greater peace of mind. The concern about the challenges associated with diagnosing and treating Lyme disease is a primary motivator for clinicians to recommend the vaccine, while the concern about getting Lyme disease is a primary motivator for consumers to desire the vaccine.

Comparative analysis of antibody responses to outer surface protein (Osp)A and OspC in dogs vaccinated with Lyme disease vaccines.

Lyme disease (LD), the most common tick-borne disease of canines and humans in N. America, is caused by the spirochete Borreliella burgdorferi. Subunit and bacterin vaccines are available for the prevention of LD in dogs. LD bacterin vaccines, which are comprised of cell lysates of two strains of B. burgdorferi, contain over 1000 different proteins and cellular constituents. In contrast, subunit vaccines are defined in composition and consist of either outer surface protein (Osp)A or OspA and an OspC chimeritope. In this study, we comparatively assessed antibody responses to OspA and OspC induced by vaccination with all canine bacterin and subunit LD vaccines that are commercially available in North America. Dogs were administered a two-dose series of the vaccine to which they were assigned (3 weeks apart): Subunit-AC, Subunit-A, Bacterin-1, and Bacterin-2. Antibody titers to OspA and OspC were determined by ELISA and the ability of each vaccine to elicit antibodies that recognize diverse OspC proteins (referred to as OspC types) assessed by immunoblot. While all of the vaccines elicited similar OspA antibody responses, only Subunit-AC triggered a robust and broadly cross-reactive antibody response to divergent OspC proteins. The data presented within provide new information regarding vaccination-induced antibody responses to key tick and mammalian phase antigens by both subunit and bacterin LD canine vaccine formulations.

Tick-Tattoo: DNA Vaccination Against B. burgdorferi or Ixodes scapularis Tick Proteins.

Introduction: Borrelia burgdorferi sensu lato (sl) is the causative agent of Lyme borreliosis. Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines. DNA tattoo vaccination with B. afzelii strain PKo OspC in mice has proven to be fully protective against B. afzelii syringe challenge and induces a favorable humoral immunity compared to recombinant protein vaccination. Alternatively, several recombinant protein vaccines based on tick proteins have shown promising effect in tick-bite infection models. In this study, we evaluated the efficacy of DNA vaccines against Borrelia OspC or tick antigens in a tick-bite infection model. Method: We vaccinated C3H/HeN mice with OspC using a codon-optimized DNA vaccine or with recombinant protein. We challenged these mice with B. burgdorferi sensu stricto (ss)-infected Ixodes scapularis nymphs. Subsequently, we vaccinated C3H/HeN mice with DNA vaccines coding for tick proteins for which recombinant protein vaccines have previously resulted in interference with tick feeding and/or Borrelia transmission: Salp15, tHRF, TSLPI, and Tix-5. These mice were also challenged with B. burgdorferi ss infected Ixodes scapularis nymphs. Results: DNA tattoo and recombinant OspC vaccination both induced total IgG responses. Borrelia cultures and DNA loads of skin and bladder remained negative in the mice vaccinated with OspC DNA vaccination, except for one culture. DNA vaccines against tick antigens Salp15 and Tix-5 induced IgG responses, while those against tHRF and TSLPI barely induced any IgG response. In addition, Borrelia cultures, and DNA loads from mice tattooed with DNA vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 were all positive. Conclusion: A DNA tattoo vaccine against OspC induced high specific IgG titers and provided near total protection against B. burgdorferi ss infection by tick challenge. In contrast, DNA tattoo vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 induced low to moderate IgG titers and did not provide protection. Therefore, DNA tattoo vaccination does not seem a suitable vaccine strategy to identify, or screen for, tick antigens for anti-tick vaccines. However, DNA tattoo vaccination is a straightforward and effective vaccination platform to assess novel B. burgdorferi sl antigen candidates in a relevant tick challenge model.

Investigating BB0405 as a novel Borrelia afzelii vaccination candidate in Lyme borreliosis.

BB0405 is a surface exposed Borrelia burgdorferi protein and its vaccination protected mice against B. burgdorferi infection. As BB0405 is highly conserved across different B. burgdorferi sensu lato species, we investigated whether vaccination with recombinant BB0405 or through intradermal bb0405 DNA tattoo vaccination could provide protection against different Borrelia species, specifically against Borrelia afzelii, the predominant B. burgdorferi sensu lato genospecies causing Lyme borreliosis across Eurasia. We immunized C3H/HeN mice with recombinant BB0405 or with a codon-optimized bb0405 DNA vaccine using the pVAC plasmid and immunized corresponding control groups mice with only adjuvant or empty vectors. We subsequently subjected these immunized mice to a tick challenge with B. afzelii CB43-infected Ixodes ricinus nymphs. Upon vaccination, recombinant BB0405 induced a high total IgG response, but bb0405 DNA vaccination did not elicit antibody responses. Both vaccine formulations did not provide protection against Borrelia afzelii strain CB43 after tick challenge. In an attempt to understand the lack of protection of the recombinant vaccine, we determined expression of BB0405 and showed that B. afzelii CB43 spirochetes significantly and drastically downregulate the expression of BB0405 protein at 37 °C compared to 33 °C, where as in B. burgdorferi B31 spirochetes expression levels remain unaltered. Vaccination with recombinant BB0405 was previously shown to protect against B. burgdorferi sensu stricto. Here we show that vaccination with either recombinant BB0405 (or non-immunogenic bb0405 DNA), despite being highly conserved among B. burgdorferi sl genospecies, does not provide cross-protection against B. afzelii, mostly likely due to downregulation of this protein in B. afzelii in the mammalian host.

Control of ixodid ticks and prevention of tick-borne diseases in the United States: The prospect of a new Lyme disease vaccine and the continuing problem with tick exposure on residential properties.

In the United States, exposure to human-biting ixodid ticks can occur while spending time on residential properties or in neighborhood green spaces as well as during recreational or occupational activities on public lands. Human-biting tick species collectively transmit >15 species of pathogenic microorganisms and the national burden of tick-borne diseases is increasing. The prospect of a new Lyme disease vaccine for use in humans provides hope for substantial reduction in the >450,000 estimated annual cases of Lyme disease but this breakthrough would not reduce cases of other tick-borne diseases, such as anaplasmosis, babesiosis, ehrlichiosis, spotted fever group rickettsiosis, and Powassan encephalitis. One intriguing question is to what extent a new Lyme disease vaccine would impact the use of personal protection measures acting broadly against tick-bites. The main tick vector for Lyme disease spirochetes in the eastern United States, Ixodes scapularis, also transmits causative agents of anaplasmosis, babesiosis, and Powassan encephalitis; and this tick species co-occurs with other human-biting vectors such as Amblyomma americanum and Dermacentor variabilis. It therefore is important that a new Lyme disease vaccine does not result in reduced use of tick-bite prevention measures, such as tick repellents, permethrin-treated clothing, and frequent tick checks. Another key issue is the continuing problem with tick exposure on residential properties, which represents a heavily used outdoor environment the residents cannot reasonably avoid and where they tend to spend large amounts of time outside. As it may not be realistic to keep up daily vigilance with personal protective measures against tick-bites on residential properties during many months of every year, homeowners may also consider the option to suppress host-seeking ticks by means of deer fencing, landscaping, vegetation management, and use of products to kill host-seeking ticks or ticks infesting rodents. When considering the full range of options for actions that can be taken to suppress host-seeking ticks on residential properties, it is clear that individual homeowners face a difficult and bewildering task in deciding what to do based on very general guidance from public health agencies (developed without the benefit of a strong evidence base) and often without ready access to local public health professionals experienced in tick control. This situation is not satisfactory but cannot be corrected without first addressing knowledge gaps regarding the impact of peridomestic tick control measures on host-seeking ticks, human tick-bites, and tick-borne diseases. In parallel with this effort, there also is a need to increase the local public health workforce with knowledge of and experience with tick control to provide better access for homeowners to sound and objective advice regarding tick control on their properties based on key characteristics of the landscaping, habitat composition, and use patterns by wild animal tick hosts as well as the residents.

Human and Veterinary Vaccines for Lyme Disease.

Lyme disease (LD) is an emerging zoonotic infection that is increasing in incidence in North America, Europe, and Asia. With the development of safe and efficacious vaccines, LD can potentially be prevented. Vaccination offers a cost-effective and safe approach for decreasing the risk of infection. While LD vaccines have been widely used in veterinary medicine, they are not available as a preventive tool for humans. Central to the development of effective vaccines is an understanding of the enzootic cycle of LD, differential gene expression of Borrelia burgdorferi in response to environmental variables, and the genetic and antigenic diversity of the unique bacteria that cause this debilitating disease. Here we review these areas as they pertain to past and present efforts to develop human, veterinary, and reservoir targeting LD vaccines. In addition, we offer a brief overview of additional preventative measures that should employed in conjunction with vaccination.