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

Abstract

Lyme disease was first characterized by Allen Steere and Stephen Malawista in 1977 [1] and has now rapidly expanded to become the most common vector-borne disease in the northern hemisphere [2, 3]. In the United States alone, there are an estimated 500 000 cases annually [2] with cumulative annual health care costs of over $1 billion [4]. This disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted to humans through the bite of an infected black-legged tick, Ixodes scapularis [5, 6]. If left untreated, Lyme disease can result in clinical symptoms involving the heart, joints, and nervous system [6]. As such, there has been a push to develop effective vaccines to prevent the tick-borne transmission of this pathogen [1, 5, 7]. In this review, we will detail the history of vaccine development using spirochetal outer surface protein A (OspA) and newer strategies—targeting the tick—to protect against B burgdorferi transmission.

VACCINES TARGETING THE SPIROCHETE

In 1990, it was first shown that active immunization of mice with a recombinant B burgdorferi protein, OspA, or the passive transfer of an OspA monoclonal antibody, could protect animals from infection with the Lyme disease agent [8, 9]. This protein was initially chosen as the vaccine target as it is a highly expressed protein on the surface of in vitro cultured B burgdorferi [10]. To facilitate survival in the differing environments of the tick vector and the vertebrate host, B burgdorferi expresses stage-specific genes in response to the varying environmental pressures [11]. Interestingly, further studies demonstrated that OspA is preferentially expressed when the spirochetes are in the tick [12] and that OspA antibodies worked by eradicating B burgdorferi in the gut of the tick [13]. Indeed, subsequent large-scale clinical trials found a 76% reduction of symptomatic Lyme disease in the vaccinated group with recombinant OspA [14], and an independent group confirmed these results in clinical trials examining the efficacy of a similar recombinant OspA vaccine termed ImmuLyme [15]. From these results, a recombinant OspA vaccine, termed LYMErix, was approved by the Food and Drug Administration (FDA) in 1998 and made available to the public. LYMErix was taken off the market in 2002, citing poor sales, public concerns regarding safety, and vaccine hesitancy. The FDA, Centers for Disease Control and Prevention, and National Institutes of Health, however, all independently examined the postmarket surveillance data [16, 17] and found the rates of reported adverse health events among vaccinated individuals were lower than in the background population [18, 19]. LYMErix remains the only approved human Lyme disease vaccine to date, highlighting both the scientific and communication challenges associated with Lyme disease vaccine development.

ONGOING SEARCH FOR B burgdorferi VACCINES

Today, the search for a vaccine targeting B burgdorferi Osps continues [20, 21]. While previous studies have demonstrated that a monovalent OspA vaccine already provides protection from infection with a wide range of B burgdorferi strains [22], a multivalent OspA vaccine encompassing variants of 6 serotypes (termed VLA15) is undergoing phase 3 trials [23–25], with the hope of providing protection against an even wider range of Lyme Borrelia species and strains that are found throughout Eurasia and North America. Preclinical studies showed that mice challenged with 4 clinically relevant Borrelia species were protected against OspA serotypes 1–6 [25]. Furthermore, published phase 1 results indicate that the VLA15 vaccine is efficacious, with mild adverse reactions [22]. VLA15 was immunogenic for all serotypes with the highest immune response at the highest dose (90 µg), with geometric mean titer ranges of 61.3–327.7 U/mL, compared to 23.8–111.5 U/mL in the nonadjuvant group [22]. The results of VLA15 thus far are promising to show human protection in widespread geographic locations. Work done by Marcinkiewicz et al targets another B burgdorferi protein, CspZ. CspZ facilitates complement evasion by recruiting a host-produced complement inhibitor, factor H [26], and this group found that immunization of mice with a mutant CspZ variant lacking this FH-binding ability prevents B burgdorferi colonization [26, 27]. Studies have also tested the efficacy of other vaccine platforms. For example, a lipid nanoparticle-encapsulated nucleoside-modified messenger RNA platform (mRNA-LNP) encoding OspA limits infection in a murine model [28]. A DNA-LNP vaccine has targeted another prevalent B burgdorferi protein, OspC. This was found to induce robust OspC-type A antibody titers, limit infection, and partially protect against Lyme disease symptoms in mice [29]. Collectively, these studies suggest that diverse B burgdorferi antigens contribute to protective immunity against the spirochete, but none of the identified targets have so far been demonstrated to be superior to OspA.

A NEW DIRECTION: ANTI-TICK VACCINES

Instead of targeting the pathogen itself, anti-tick vaccines are an alternative approach and have been developed to inhibit tick feeding and prevent pathogen transmission. These vaccines are particularly enticing, as they may potentially prevent the transmission of a variety of tick-borne pathogens with a single vaccine by targeting the vector itself. Additionally, anti-tick vaccines should not prompt the evolution of resistance, as they would only impact individual ticks feeding on a vaccinated host and would not subject the wider tick population to selective pressures exerted by broader acaricidal interventions [30]. In fact, anti-tick vaccines have been successfully implemented in livestock [31, 32]: multiple vaccines were developed during the 1990s to target Bm86, a protein in the gut of Rhipicephalus microplus, a tick that heavily parasitizes cattle in tropical regions such as Cuba, Mexico, Brazil, and Australia [32, 33]. These vaccines have been successful in inhibiting tick feeding and pathogen transmission in cattle and sheep. Now, vaccines for human use are being developed, with the goal of preventing tick feeding and thus preventing tick-borne pathogen transmission.

Following repeated exposure to ticks, noncanonical hosts such as guinea pigs and humans develop anti-tick immunity, known as acquired tick resistance [34]. This is characterized by erythema at the bite site and inhibited tick feeding, as indicated by reduced engorgement and fecundity [35, 36]. Hard ticks, such as one of the primary vectors of Lyme disease, I scapularis, have a prolonged feeding period, lasting several days. To facilitate this feeding, the ticks inject the host with a cocktail of pharmacologically active salivary components, including analgesics, anticoagulants, and immune inhibitors, that enable the tick to feed unnoticed [37]. It has been found that acquired tick resistance is due in part to the host's humoral immune response to these salivary antigens [36, 38]. Furthermore, tick resistance limits or prevents tick-to-host transmission of pathogens [39]. Therefore, there has been a push to develop vaccines targeting tick salivary proteins, with the goal of preventing pathogen transmission by inhibiting tick feeding.

Matias et al focused on one I scapularis salivary anticoagulant, Salp14, as a model antigen to observe tick immunity and test different vaccine platforms [40]. In this study, guinea pigs were immunized with Salp14 in the form of mRNA-LNPs, plasmid DNA, or recombinant protein. It was found that vaccination with the mRNA-LNP Salp14 platform induced the strongest immune response upon tick feeding, as measured by the degree of erythema at the bite site [40]. While there was immune response to Salp14 alone, the inhibition of tick feeding was not as robust as naturally acquired tick resistance and thus multiple salivary components are likely necessary to develop a successful anti-tick vaccine [40].

Building upon the Salp14 results, a similar anti-tick mRNA-LNP vaccine was developed, encompassing 19 I scapularis salivary proteins, termed 19ISP [41]. This vaccine resulted in rapid development of erythema at the bite site, early tick detachment, and decreased engorgement weights [41]. Along with poor tick feeding, rapid erythema is a valuable component of an anti-tick vaccine, as the redness and irritation alert the host to the presence of the feeding tick. Indeed, when ticks were removed from the guinea pigs at the onset of erythema, B burgdorferi transmission was prevented. Now, a smaller cocktail of 12 salivary proteins, termed 12ISP, has been successfully tested in guinea pigs, with similar findings of antigenicity and erythema [42]. Furthermore, this study tested mRNA-LNP platforms containing a smaller subset of targets, but these were unable to generate tick resistance, supporting the need for a cocktail vaccine. Overall, these findings demonstrate that an mRNA-LNP platform encoding a cocktail of tick salivary antigens is an effective method for reducing pathogen transmission by targeting the host-vector interaction, with promising results in the guinea pig model.

Alongside the work done with mRNA-LNPs, the ANTIDotE (Anti-tick Vaccines to Prevent Tick-borne Diseases in Europe) team is a European Commission-funded consortium of institutions that aims to develop and evaluate anti-tick vaccine candidates that target I. ricinus—the most common European vector of Lyme disease and other tick-borne diseases [43]. This project works to integrate a multidisciplinary one-health approach to vaccine development [43, 44]. Furthermore, pharmacoeconomic models generated find that anti-tick vaccination is highly cost-effective, by protecting against multiple tick-borne pathogens [45]. Such pharmacoeconomic evaluation is an insightful tool to model the economic impact, clinical, and public health value of a proposed vaccine design. Therefore, an emphasis on the fact that anti-tick vaccination prevents a multitude of tick-borne diseases, alongside integrative public health approaches, is a promising communication strategy to overcome historical challenges in Lyme disease vaccination acceptance.

FUTURE DIRECTIONS

The history of Lyme disease vaccinations has included successes, challenges, lessons, and opportunities for innovations in the field. Today, the shift to vaccines targeting the tick itself is an innovative and promising strategy to prevent multiple tick-borne pathogens. However, more work is needed to translate these findings from laboratory systems to public implementation. For one, the individual contributions of each antigen in the 19ISP and 12ISP cocktails are unknown. This must be determined to whittle down the cocktail and develop an optimized vaccine that does not contain excess targets. Conversely, other antigens not included in these cocktails are known to induce tick resistance [33, 46] and should be studied as potential vaccine targets. Furthermore, while anti-tick vaccines have the potential to prevent transmission of a range of pathogens with one vaccine, current studies have only focused on B burgdorferi. B burgdorferi is transmitted slowly into the host, while other pathogens like Powassan virus are transmitted rapidly upon attachment [47, 48]. It stands to be determined whether current anti-tick vaccine strategies are effective against the transmission of more quickly transmitting pathogens. Finally, humans are an incidental host of tick-borne diseases and tick vectors, so it should be studied whether these vaccines can be effectively implemented in populations of reservoir hosts to limit disease prevalence [49].

The history of the LYMErix OspA vaccine and subsequent vaccine trials have highlighted the importance of reducing structural barriers to vaccine information and uptake. In Lyme disease and anti-tick vaccines, there have been challenges to define the populations who should receive a vaccine. As seen in recent vaccine uptake during the coronavirus disease 2019 (COVID-19) pandemic, insecure recommendations on the safety and efficacy of the vaccine and poor scientific communication further vaccine hesitancy and reduce uptake [50]. Therefore, sufficient communication and public health recommendations on the anti-tick and Lyme disease vaccines is necessary to move forward with successful candidates. Across the 50-year race to uncover a Lyme disease vaccine, the future holds promise through a multitude of innovative strategies conquering pathogen transmission and acquired tick immunity.

Notes

Financial support. This work was supported by the National Institutes of Health (grant numbers AI165499 and AI138949); the Steven and Alexandra Cohen Foundation; and the Howard Hughes Medical Institute Emerging Pathogens Initiative.

Supplement sponsorship. This article appears as part of the supplement “Lyme Disease,” sponsored by the Lyme Disease Program at Massachusetts General Hospital and a generous gift from the Morse family.

Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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