Vaccination to Prevent Lyme Disease: A Movement Towards Anti-Tick Approaches.

Lyme disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted by Ixodes spp ticks. The rise in Lyme disease cases since its discovery in the 1970s has reinforced the need for a vaccine. A vaccine based on B burgdorferi outer surface protein A (OspA) was approved by the Food and Drug Administration (FDA) several decades ago, but was pulled from the market a few years later, reportedly due to poor sales, despite multiple organizations concluding that it was safe and effective. Newer OspA-based vaccines are being developed and are likely to be available in the coming years. More recently, there has been a push to develop vaccines that target the tick vector instead of the pathogen to inhibit tick feeding and thus prevent transmission of tick-borne pathogens to humans and wildlife reservoirs. This review outlines the history of Lyme disease vaccines and this movement to anti-tick vaccine approaches.

Antibody-mediated immunological memory correlates with long-term Lyme veterinary vaccine protection in mice.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne illness in the United States. Despite the rise in Lyme disease incidence, there is no vaccine against B. burgdorferi approved for human use. Little is known about the immune correlates of protection needed to prevent Lyme disease. In this work, a mouse model was used to characterize the immune response and compare the protection provided by two USDA-approved vaccines for use in canines: Duramune (bacterin vaccine) and Vanguard crLyme (subunit vaccine composed of two outer surface proteins, OspA and OspC). C3H/HeNCrl mice were immunized with two doses of either Duramune or Vanguard, and immune responses and protection against B. burgdorferi were assessed in short (35 days) and long-term (120 days) studies. Flow cytometry, ELISPOT detection of antibody-producing cells, and antibody affinity studies were performed to identify correlates of vaccine-mediated protection. Both vaccines induced humoral responses, with high IgG titers against B. burgdorferi. However, the levels of anti-B. burgdorferi antibodies decayed over time in Vanguard-vaccinated mice. While both vaccines triggered the production of antibodies against both OspA and OspC, antibody levels against these proteins were also lower in Vanguard-vaccinated mice 120 days post-vaccination. Both vaccines only provided partial protection against B. burgdorferi at the dose used in this model. The protection provided by Duramune was superior to Vanguard 120 days post-vaccination, and was characterized by higher antibody titers, higher abundance of long-lived plasma cells, and higher avidity antibodies than Vanguard. Overall, these studies provide insights into the importance of the humoral memory response to veterinary vaccines against Lyme disease and will help inform the development of future human vaccines.

Optimisation of dose level and vaccination schedule for the VLA15 Lyme borreliosis vaccine candidate among healthy adults: two randomised, observer-blind, placebo-controlled, multicentre, phase 2 studies.

BACKGROUND: Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1-6, which are associated with the most common pathogenic Borrelia species in Europe and North America. METHODS: Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18-65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 µg (study one only), 135 µg, or 180 µg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 µg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed. FINDINGS: For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 µg VLA15, 215 to 135 µg, 205 to 180 µg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 µg VLA15, 100 to 180 µg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4-119·0) to 267·4 units per mL (serotype 3; 194·8-367·1) for 90 µg VLA15, 101·9 (serotype 1; 87·1-119·4) to 283·2 units per mL (serotype 3; 248·2-323·1) for 135 µg, and 115·8 (serotype 1; 98·8-135·7) to 308·6 units per mL (serotype 3; 266·8-356·8) for 180 µg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9-361·0) to 545·2 units per mL (serotype 2; 431·8-688·4) for 135 µg VLA15 and 274·7 (serotype 1; 209·4-360·4) to 596·8 units per mL (serotype 3; 471·9-754·8) for 180 µg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91-96 vs 26%, 19-34; study two: 96%, 93-98 vs 35%, 24-49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65-73 vs 43%, 34-52; study two: 74%, 67-80 vs 51%, 38-64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48-57) of participants in the VLA15 groups and 52% (43-60) of those in the placebo groups; for study two these were 65% (58-71) and 69% (55-80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1-4; study two: 4%, 2-7) and adverse events of special interest (study one: 1%, 0-2; study two: 1%, 0-3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported. INTERPRETATION: VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 µg dose and 0-2-6-month schedule, which was associated with the greatest immune responses. FUNDING: Valneva.

Using the Health Belief Model to understand intention to vaccinate for Lyme disease in the United States.

AIMS: A growing number of Lyme disease (LD) cases in the U.S. are reported in states neighbouring those with high-incidence (>10 cases per 100,000 population) rates. Considering the evolving epidemiology, high-incidence counties in many of these "neighbouring states," and the forthcoming vaccines, understanding the drivers of vaccination intention is critical, particularly how drivers of intention in neighbouring states vary relative to regions currently classified as high incidence. This study uses the Health Belief Model (HBM) to determine the key drivers associated with vaccine intention for U.S. adults and caregivers of children residing in neighbouring states. METHODS AND RESULTS: Using an established panel with quotas for age, sex, race/ethnicity and urbanity, we surveyed 887 adults and 822 caregivers of children residing in U.S. neighbouring states. Survey items included measures of intention and HBM constructs, all of which were assessed using 5-point Likert scales. We subsequently used structural equation modelling to understand the influence of the HBM constructs on LD vaccine intention. Estimates from structural equation modelling show that the HBM constructs explain much of the variation in intention to vaccinate against LD. Intentions to vaccinate for both adults and caregivers are positively influenced by cues to action, perceived susceptibility of LD, and perceived benefits to vaccination. Both are also negatively influenced by perceived barriers to vaccination. The caregiver's intention to vaccinate is also positively influenced by the perceived severity of LD. CONCLUSION: The intention to vaccinate for respondents residing in LD neighbouring states is strongly influenced by recommendations from healthcare providers or the Centers for Disease Control and Prevention (CDC). As incidence rises in neighbouring states and the need to prevent disease becomes more overt, public health officials should strongly recognize the influence of healthcare providers and CDC recommendations on intention to vaccinate against LD.

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.

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.

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.

Intention to vaccinate for Lyme disease using the Health Belief Model.

AIMS: Lyme disease (LD) cases in the United States are estimated to be approaching 500,000 annually. Protective measures, such as repellent use and wearing protective clothing are recommended by public health officials. However, no protective measure has been proven to be consistently effective, partly because they require consistent and persistent behaviour change. While safe and effective vaccines are in development, it is unclear what factors influence the intention to vaccinate against LD. This study uses the Health Belief Model (HBM) framework to determine key drivers associated with vaccine intention. The HBM is widely applied in public health research and uses the following constructs: perceived susceptibility and severity of disease, perceived benefits and barriers to disease prevention, and cues to action for disease prevention to predict health behaviours. To date, the HBM framework has not been applied to vaccination intention for LD. METHODS AND RESULTS: Data were collected from 874 adults and 834 caregivers of children residing in US states endemic to LD. Sampling adults and caregivers allows us to explore how the intention to vaccinate differs among those at-risk. Estimates from structural equation modelling (SEM) show that the HBM constructs explain much of the variation in intention to vaccinate against LD. Both adult and caregiver intentions to vaccinate are positively influenced by cues to action, perceived susceptibility of LD, and perceived benefits to vaccination. However, there is variation in the influence of constructs across the samples. Caregiver's intention to vaccinate is positively influenced by the perceived severity of LD and negatively influenced by safety concerns about the vaccine, whereas adult intention is negatively influenced by perceived barriers to vaccination. CONCLUSION: A strong relationship of cues to action on vaccine intention in samples of adults and caregivers suggests the importance of a recommendation from a healthcare provider or the Centers for Disease Control and Prevention (CDC).

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.

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.

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.