Construction and analysis of variants of a polyvalent Lyme disease vaccine: Approaches for improving the immune response to chimeric vaccinogens

Earnhart, Christopher G.; Marconi, Richard T.

doi:10.1016/j.vaccine.2006.12.051

Cited by 39 publications

(43 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The goal of our efforts is to develop a chimeric polyvalent vaccine construct that consists of the type-specific, protective epitopes of those OspC types associated with invasive infection in humans. As proof of principle, we previously developed a construct that incorporates epitopes from OspC types A, B, K, and D (11)(12)(13). This construct elicited bactericidal antibody against spirochetes ex-FIG.…”

mentioning

confidence: 99%

OspC Phylogenetic Analyses Support the Feasibility of a Broadly Protective Polyvalent Chimeric Lyme Disease Vaccine

Earnhart

Marconi

2007

Clin Vaccine Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

OspC Phylogenetic Analyses Support the Feasibility of a Broadly Protective Polyvalent Chimeric Lyme Disease Vaccine

Earnhart

Marconi

2007

Clin Vaccine Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…One possible approach to consider is the development of a chimeric FhbB protein harboring the major FhbB types. The utility of chimeric proteins to elicit bactericidal Ab against diverse strains of the Lyme disease spirochetes has been demonstrated in several studies (41)(42)(43). It may also be possible to exploit Ab directed at FhbB as a therapeutic tool for periodontal disease.…”

Section: Discussionmentioning

confidence: 99%

The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin

et al. 2016

Self Cite

View full text Add to dashboard Cite

The Treponema denticola FhbB protein contributes to immune evasion by binding factor H (FH). Cleavage of FH by the T. denticola protease, dentilisin, may contribute to the local immune dysregulation that is characteristic of periodontal disease (PD). Although three FhbB phyletic types have been defined (FhbB1, FhbB2, and FhbB3), the in vivo expression patterns and antigenic heterogeneity of FhbB have not been assessed. Here, we demonstrate that FhbB is a dominant early antigen that elicits FhbB type-specific antibody (Ab) responses. Using the murine skin abscess model, we demonstrate that the presence or absence of FhbB or dentilisin significantly influences Ab responses to infection and skin abscess formation. Competitive binding analyses revealed that ␣-FhbB Ab can compete with FH for binding to T. denticola and block dentilisin-mediated FH cleavage. Lastly, we demonstrate that dentilisin cleavage sites reside within critical functional domains of FH, including the complement regulatory domain formed by CCPs 1 to 4. Analysis of the FH cleavage products revealed that they lack cofactor activity. The data presented here provide insight into the in vivo significance of dentilisin, FhbB and its antigenic diversity, and the potential impact of FH cleavage on the regulation of complement activation. P eriodontal disease (PD) of infectious etiology is a significant human and veterinary health concern. PD is a chronic inflammatory disease that degrades tissue and reabsorbs bone that surrounds and supports teeth, leading to endentulism (1). PD results from a dysbiosis of the polymicrobial community of the subgingival crevice. The transition of the bacterial population from predominantly Gram-positive organisms to destructive anaerobic spirochetes and Gram-negative organisms (2-4) is accompanied by local dysregulation of immunoregulatory mechanisms (5-8). Specific periopathogens, including Treponema denticola and Porphyromonas gingivalis, are thought to play leading roles in this process (8)(9)(10). This study is focused on T. denticola, an anaerobic, proteolytic (tissue degrading) spirochete of humans that is a dominant periopathogen and member of the "red microbial complex" (4, 11). T. denticola and other oral treponemes are also key players in root canal and endodontic infections (12, 13).Periopathogens thrive in the subgingival crevice, an anatomical niche bathed in gingival crevicular fluid (GCF). GCF is derived from serum and local tissue exudate (14) and is rich in immune effectors, including activated complement, C-reactive protein, opsonins (C3b and iC3b), anaphylatoxins, and proinflammatory cytokines (reviewed in references 1 and 15). T. denticola evades complement mediated destruction by binding factor H (FH), a negative regulator of the complement system (9, 16-18). FH, an abundant 150-kDa serum glycoprotein (ϳ300 g ml of serum Ϫ1 ) (19,20), consists of 20 imperfect repeat domains (CCPs) of 50 to 60 amino acids each that comprise different functional domains (21-25).The FH binding protein of T. denticola, Fh...

show abstract

“…The OspA vaccine was demonstrated to be safe, but it was withdrawn from the market only a few years after introduction, as acceptance by the public was low because of a number of factors (38)(39)(40)(41). Several candidate vaccines investigated more recently have targeted proteins produced in abundant amounts by B. burgdorferi grown in the laboratory and some that are exposed on the bacterial surface, although only some of these proteins have also been assigned activities or functions in vitro and/or in vivo (6,8,(42)(43)(44)(45)(46)(47)(48). An immune response that blocks the function of a protein may prove more efficacious in preventing disease than a response that does not interfere with function.…”

Section: Discussionmentioning

confidence: 99%

“…A single dose of lyophilized whole-cell Borrelia produced limited protection as a vaccine in hamsters (4,5), and the authors suggested that further studies were warranted. In fact, whole-cell vaccines are currently available for veterinary use, but a less reactogenic multivalent subunit vaccine has more recently been developed (6)(7)(8). Live attenuated flagellumless Borrelia cells in a high-passage-number noninfectious background also elicited protective immunity in mice for a limited duration (9).…”

mentioning

confidence: 99%

Live Attenuated Borrelia burgdorferi Targeted Mutants in an Infectious Strain Background Protect Mice from Challenge Infection

Hahn

Padmore

Ristow

et al. 2016

Clin Vaccine Immunol

View full text Add to dashboard Cite

Borrelia burgdorferi, B. garinii, and B. afzelii are all agents of Lyme disease in different geographic locations. If left untreated, Lyme disease can cause significant and long-term morbidity, which may continue after appropriate antibiotic therapy has been administered and live bacteria are no longer detectable. The increasing incidence and geographic spread of Lyme disease are renewing interest in the vaccination of at-risk populations. We took the approach of vaccinating mice with two targeted mutant strains of B. burgdorferi that, unlike the parental strain, are avirulent in mice. Mice vaccinated with both strains were protected against a challenge with the parental strain and a heterologous B. burgdorferi strain by either needle inoculation or tick bite. In ticks, the homologous strain was eliminated but the heterologous strain was not, suggesting that the vaccines generated a response to antigens that are produced by the bacteria both early in mammalian infection and in the tick. Partial protection against B. garinii infection was also conferred. Protection was antibody mediated, and reactivity to a variety of proteins was observed. These experiments suggest that live attenuated B. burgdorferi strains may be informative regarding the identification of protective antigens produced by the bacteria and recognized by the mouse immune system in vivo. Further work may illuminate new candidates that are effective and safe for the development of Lyme disease vaccines. L yme disease (LD) is the most common vector-borne disease in North America. In addition to Borrelia burgdorferi, the major LD agent in North America, B. garinii and B. afzelii are agents of LD in Europe and Asia. While antibiotic treatment is available and effective in the majority of cases diagnosed early in infection, significant morbidity is associated with LD, in some cases, with symptoms continuing beyond the standard antibiotic therapy regimens. In addition, the Centers for Disease Control and Prevention (CDC) recently investigated possible B. burgdorferi infection as a trigger of sudden cardiac death in relatively young, active people (1, 2). Recent estimates from the CDC also suggest that the number of cases may be as much as 10-fold higher than the number actually reported (3), with current estimates of ϳ300,000 cases/year in the United States.No vaccine against LD is currently available for use in humans. A single dose of lyophilized whole-cell Borrelia produced limited protection as a vaccine in hamsters (4, 5), and the authors suggested that further studies were warranted. In fact, whole-cell vaccines are currently available for veterinary use, but a less reactogenic multivalent subunit vaccine has more recently been developed (6-8). Live attenuated flagellumless Borrelia cells in a high-passage-number noninfectious background also elicited protective immunity in mice for a limited duration (9). A vaccine targeting outer surface protein A (OspA) (10, 11), an abundant protein on the surface of the bacteria grown in the laboratory, was av...

show abstract

Construction and analysis of variants of a polyvalent Lyme disease vaccine: Approaches for improving the immune response to chimeric vaccinogens

Cited by 39 publications

References 55 publications

OspC Phylogenetic Analyses Support the Feasibility of a Broadly Protective Polyvalent Chimeric Lyme Disease Vaccine

OspC Phylogenetic Analyses Support the Feasibility of a Broadly Protective Polyvalent Chimeric Lyme Disease Vaccine

The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin

Live Attenuated Borrelia burgdorferi Targeted Mutants in an Infectious Strain Background Protect Mice from Challenge Infection

Contact Info

Product

Resources

About