Lyme Disease and Borrelia burgdorferi

Borrelia burgdorferi

Borrelia burgdorferi (B. Burgdorferi), an intermediate between bacteria and protozoa, belongs to the class Spirochaetales, order Spirochaetales, family Splrochaetaceaceace, and genus Borrelia. Borrelia burgdorferi is the main cause of Lyme disease, and there are three pathogenic genotypes: Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which vary greatly in their pathogenicity and in the clinical manifestations of the infection.

B. burgdorferi is a microaerobic bacterium consisting of single cells loosely coiled, generally with 3~10 sparse and irregular spirals, wavy, slightly pointed at both ends. Its movement is active, with twisting, tumbling, shaking and other kinds of movement. In addition to having a typical bacterial plasma membrane, it has an outer membrane known as the outer membrane sheath. The protoplasmic cylinder consisting of the nuclear region and cytoplasm and the outer membrane sheath is known as the periplasm and contains flagella. The outer membrane of B. burgdorferi consists of outer membrane proteins and phospholipids and lacks lipopolysaccharides, whereas outer membrane proteins mainly consist of abundant outer surface lipoproteins and intact transmembrane proteins, which are capable of eliciting inflammatory responses in human host cells.

Figure 1. Borrelia burgdorferi morphology and cellular architecture
(Source: Steere AC, et al. 2016)

The genome of B. burgdorferi is relatively small, about 1.5 Mb, and it contains a linear chromosome 950 Kb in length with at least 21 additional chromosomal DNA elements or plasmids. B. burgdorferi possesses the largest known number of plasmid-associated genes for pathogenicity, including the outer surface protein gene (Osp). Its virulence determinants are present both on linear chromosomes and on linear and circular plasmids. Virulence genes on chromosomes include p66, bgp, plzA, rpoN, rpoS, or bosR, whereas virulence-related genes present on plasmids encode proteins such as DbpA/B, BBK32, OspC, PncA, and VlsE.

Lyme Disease Symptoms

Lyme disease is a systemic infection with clinical manifestations often involving the skin, joints, nervous system, and heart that enter the clinical phase after a period of incubation. Patients with untreated Lyme disease are categorized into three stages based on their clinical presentation: localized skin lesions (stage I), spread of infection (stage II), and persistence of infection (stage III). Symptoms of each stage are often seen separately, but there are cases in which all three stages occur together.

EM is often the first symptom of Lyme disease and is a unique clinical feature of the disease. EM is most commonly characterized by circumscribed erythema with a pale, scarlet or pale hard center in typical cases, and blistering or necrosis in the center in atypical cases. In the localized lesion stage patients are often accompanied by non-specific symptoms such as fever and chills. The lesions usually last about 3 weeks and improve or dissipate on their own without treatment. Within days or weeks of the bite, B. burgdorferi can spread to other organs throughout the body via the bloodstream or lymph. It has been reported in the literature that 2% to 3% of patients with Lyme disease skip the localized lesion stage and progress directly to the spread of infection, with facial nerve palsy and cranial neuropathy as the first symptoms. Persistent infection is defined as a chronic infection that has persisted or recurred for at least 6 months and manifests itself primarily as rheumatic symptoms. Early rheumatic symptoms occur when the pathogen spreads to the joints, bones and muscles. Late rheumatic symptoms are mainly characterized by arthritis, intermittent joint swelling and pain. The infection mainly affects the large joints, especially the knee joint. The disease is recurrent and prolonged, and eventually develops into joint deformity, limiting movement.

Figure 3. Possible disease progression after a tick bite
(Source: Kullberg BJ, et al. 2020)

Lyme Disease Vaccine

Although a great deal of knowledge has been acquired about the pathogens of the disease, an effective strategy to reliably overcome LD has yet to be found. There is currently no vaccine available for human use. Multiple genes shared by B. burgdorferi show high sequence variability among LD spirochete species, with genes required for optimal infectivity often differing significantly at the nucleotide and amino acid levels. This variability complicates the design of effective immunization strategies, including vaccines, because immune responses do not protect all infected species to the same degree. Therefore, current vaccine development focuses on multivalent protein vaccine development against all common serotypes of B. burgdorferi. VLA15, the only LD vaccine candidate in late clinical development, targets OspA and provides protection against the six prevalent OspA serotypes expressed by B. burgdorferi common in North America and Europe.

To address the protein variability observed in different strains and species of B. burgdorferi, researchers have been working to create a multivalent chimeric vaccine that provides protection against different species of LD, aiming to address the inherent heterogeneity of the pathogen. OspA-based multivalent formulations are a common target in current vaccine development. To fabricate self-assembling nanoparticles, OspA is combined with bacterial ferritin. These OspA-ferritin nanoparticles induce potent, long-lasting antibody responses against major serotypes in mice and non-human primates. In addition, to achieve broad protection against a single recombinant antigen, a strategy known as grafting or epitope remodeling has been successfully used to produce neutralizing antibodies against six of the most clinically relevant OspA serotypes.

In addition to vaccines based on recombinant protein technology, DNA tattoos and lipid nanoparticle-encapsulated DNA vaccines are a promising LD prevention strategy. DNA vaccines offer a number of potential advantages over traditional strategies, such as the ability to activate both B-cell and T-cell responses, enhanced vaccine stability, the absence of any infectious agents, and the immediacy of mass production.

Table 1. Examples of promising types of Lyme disease vaccine development

(Source: Pavia CS, et al. 2024)