Development and optimization of OspC chimeritope vaccinogens for Lyme disease

Izac, Jerilyn R.; O’Bier, Nathaniel S.; Oliver, Lee D.; Camire, Andrew C.; Earnhart, Christopher G.; Rhodes, DeLacy V. L.; Young, Brandon F.; Parnham, Stuart; Davies, Christopher; Marconi, Richard T.

doi:10.1016/j.vaccine.2020.01.027

Cited by 28 publications

(34 citation statements)

References 70 publications

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“…The constructs encoding His-tagged EplA and P28 were transformed into E. coli BL21 (DE3) for protein production, and purification by immobilized metal-affinity chromatography as described (Mcdowell et al, 2009 ; Miller et al, 2011 ). His-EplA and His-P28 were used for generating rat polyclonal antisera as described previously (Izac et al, 2020 ) and was performed under the approval of the Institutional Animal Care and Use Committee at Virginia Commonwealth University (protocol number AM10000387). Keyhole limpet hemocyanin-conjugated peptides corresponding to EplA 95−104 and ECH_0462 53−68 were synthesized and injected into rabbits to yield monospecific antiserum against each antigen by New England Peptide (Gardner, MA).…”

Section: Methodsmentioning

confidence: 99%

Ehrlichia chaffeensis EplA Interaction With Host Cell Protein Disulfide Isomerase Promotes Infection

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Izac

Naimi

et al. 2020

Front. Cell. Infect. Microbiol.

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Ehrlichia chaffeensis is an obligate intracellular bacterium that invades monocytes to cause the emerging and potentially severe disease, monocytic ehrlichiosis. Ehrlichial invasion of host cells, a process that is essential for the bacterium's survival and pathogenesis, is incompletely understood. In this study, we identified ECH_0377, henceforth designated as EplA (E. chaffeensis PDI ligand A) as an E. chaffeensis adhesin that interacts with host cell protein disulfide isomerase (PDI) to mediate bacterial entry into host cells. EplA is an outer membrane protein that E. chaffeensis expresses during growth in THP-1 monocytic cells. Canine sera confirmed to be positive for exposure to Ehrlichia spp. recognized recombinant EplA, indicating that it is expressed during infection in vivo. EplA antiserum inhibited the bacterium's ability to infect monocytic cells. The EplA-PDI interaction was confirmed via co-immunoprecipitation. Treating host cell surfaces with antibodies that inhibit PDI and/or thioredoxin-1 thiol reductase activity impaired E. chaffeensis infection. Chemical reduction of host cell surfaces, but not bacterial surfaces with tris(2-carboxyethyl)phosphine (TCEP) restored ehrlichial infectivity in the presence of the PDI-neutralizing antibody. Antisera specific for EplA C-terminal residues 95-104 (EplA 95−104) or outer membrane protein A amino acids 53-68 (OmpA 53−68) reduced E. chaffeensis infection of THP-1 cells. Notably, TCEP rescued ehrlichial infectivity of bacteria that had been treated with anti-EplA 95−104 , but not anti-EcOmpA 53−68. These results demonstrate that EplA contributes to E. chaffeensis infection of monocytic cells by engaging PDI and exploiting the enzyme's reduction of host cell surface disulfide bonds in an EplA C-terminus-dependent manner and identify EplA 95−104 and EcOmpA 53−68 as novel ehrlichial receptor binding domains.

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Section: Methodsmentioning

confidence: 99%

Ehrlichia chaffeensis EplA Interaction With Host Cell Protein Disulfide Isomerase Promotes Infection

Green

Izac

Naimi

et al. 2020

Front. Cell. Infect. Microbiol.

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“…To overcome OspC diversity, chimeric epitope-based recombinant proteins referred to as chimeritopes were developed that consist of L5 and H5 epitopes derived from different OspC types. The immunogenicity of these unique proteins was initially assessed in mice and rats [43] , [44] , [45] , [46] . OspC chimeritopes have been demonstrated to elicit Abs that recognize diverse OspC types [46] .…”

Section: Introductionmentioning

confidence: 99%

“…The immunogenicity of these unique proteins was initially assessed in mice and rats [43] , [44] , [45] , [46] . OspC chimeritopes have been demonstrated to elicit Abs that recognize diverse OspC types [46] . VANGUARD®crLyme (Zoetis) canine LD vaccine, which is the subject of this report, consists of an OspC chimeritope (designated as Ch14) and OspA.…”

Section: Introductionmentioning

confidence: 99%

VANGUARD®crLyme: A next generation Lyme disease vaccine that prevents B. burgdorferi infection in dogs

et al. 2020

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Lyme disease, a public health threat of significance to both veterinary and human medicine, is caused by the tick ( Ixodes ) transmitted spirochete, Borreliella burgdorferi . Here we report on the immunogenicity and efficacy of VANGUARD®crLyme (Zoetis), the most recent canine Lyme disease vaccine to be approved by the United States Department of Agriculture. VANGUARD®crLyme is a subunit vaccine consisting of outer surface protein A (OspA) and a recombinant outer surface protein C (OspC) based-chimeric epitope protein (chimeritope) that consists of at least 14 different linear epitopes derived from diverse OspC proteins. The combination of OspA and the OspC chimeritope (Ch14) in the vaccine formulation allows for the development of humoral immune responses that work synergistically to target spirochetes in both ticks and in mammals. Immunogenicity was assessed in purpose-bred dogs. A two-dose vaccination protocol resulted in high antibody titers to OspA and Ch14 and vaccinal antibody reacted with 25 different recombinant OspC variants. Efficacy was demonstrated using an Ixodes scapularis -purpose bred dog challenge model. Vaccination with VANGUARD®crLyme provided protection against infection and prevented the development of clinical manifestations and histopathological changes associated with Lyme disease.

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“…Lyme disease (LD), the most common vector-borne disease of canines and humans in North America [1] , is caused by the spirochete Borreliella burgdorferi (previously classified as Borrelia burgdorferi ) [2] , [3] , [4] . VANGUARD®crLyme (Zoetis) is a multivalent subunit vaccine consisting of a proprietary formulation of a modified outer surface protein A (OspA) and a custom designed outer surface protein C (OspC) derived protein referred to as a chimeritope [5] , [6] , [7] . Chimeritopes are recombinant proteins consisting of a series of defined linear epitopes derived from different protein variants that are incorporated into a single protein [7] .…”

Section: Introductionmentioning

confidence: 99%

“…VANGUARD®crLyme (Zoetis) is a multivalent subunit vaccine consisting of a proprietary formulation of a modified outer surface protein A (OspA) and a custom designed outer surface protein C (OspC) derived protein referred to as a chimeritope [5] , [6] , [7] . Chimeritopes are recombinant proteins consisting of a series of defined linear epitopes derived from different protein variants that are incorporated into a single protein [7] . Chimeritopes can be custom designed to elicit broad antibody (Ab) responses to one or more pathogens.…”

Section: Introductionmentioning

confidence: 99%

Field safety study of VANGUARD®crLyme: A vaccine for the prevention of Lyme disease in dogs

et al. 2020

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Here we report the results of a large-scale pre-license safety study in which two serials of VANGUARD®crLyme, a vaccine for canine Lyme disease, were tested in its target population (dogs) under the conditions of its intended use. Six-hundred and twenty dogs, from three distinct geographic regions of the United States were enrolled in this study with each receiving two doses of vaccine by subcutaneous injection 3 to 4 weeks apart. Approximately one-third of the dogs were of minimum age (≤8 weeks of age) to meet regulatory requirements. Safety was evaluated by observation of local and systemic reactions for at least 10 days after each vaccination. Abnormal health events (AHEs) occurred at low frequencies and no serious AHEs were observed. The results demonstrated that VANGUARD®crLyme is safe for use in healthy dogs 8 weeks of age or older.

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Development and optimization of OspC chimeritope vaccinogens for Lyme disease

Cited by 28 publications

References 70 publications

Ehrlichia chaffeensis EplA Interaction With Host Cell Protein Disulfide Isomerase Promotes Infection

Ehrlichia chaffeensis EplA Interaction With Host Cell Protein Disulfide Isomerase Promotes Infection

VANGUARD®crLyme: A next generation Lyme disease vaccine that prevents B. burgdorferi infection in dogs

Field safety study of VANGUARD®crLyme: A vaccine for the prevention of Lyme disease in dogs

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